See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/238158826

Dual infection with HIV-1 and HIV-2: Double trouble or destructive

interference?

Article  in  HIV Therapy · May 2010

DOI: 10.2217/hiv.10.26

CITATIONS READS

21 204

4 authors, including:

Thushan de Silva Carla van Tienen

The University of Sheffield Erasmus MC
109 PUBLICATIONS   894 CITATIONS    58 PUBLICATIONS   525 CITATIONS   

SEE PROFILE SEE PROFILE

Sarah Rowland-Jones
University of Oxford
480 PUBLICATIONS   28,057 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

interaction HIV-2 and HIV-1 View project

Bronchopulmonary function in response to azithromycin treatment for chronic lung disease in HIV-infected children (BREATHE) View project

All content following this page was uploaded by Thushan de Silva on 13 January 2016.

The user has requested enhancement of the downloaded file.

Review

Dual infection with HIV‑1 and HIV‑2: double

trouble or destructive interference?
HIV‑1 and HIV‑2 are two related retroviruses and, in regions where both infections are endemic, HIV‑1/2 dual infection
can occur. Several important questions arise about the interplay between these two viruses in a single host, including:
what is the potential for HIV‑1–HIV‑2 recombinants to form, are there synergistic or inhibitory mechanisms that
result in distinct viral replication dynamics when compared with HIV‑1 or HIV‑2 monoinfected individuals and what
are the factors to consider when choosing antiretroviral regimes in HIV‑1/2 dual-infected individuals? We summarize
the relevant evidence to answer these questions, as well as indentify trends in prevalence and how the natural history
of HIV‑1/2 dual infection differs from that of HIV‑1 or HIV‑2 monoinfection. The epidemiological and in vitro evidence
pertaining to the question of whether HIV‑2 infection may protect against HIV‑1 superinfection will also be addressed.

of
KEYWORDS: antiretroviral therapy n coinfection n cross-reactive n dual infection n HIV‑1 Thushan I de Silva1,2†,
n HIV‑2 n mortality n prevalence n recombination Carla van Tienen1,
Sarah L Rowland-Jones3

HIV‑1 and HIV‑2 are two closely related ret‑
roviruses, yet infection with either virus results
in contrasting immunopathogenesis, and con‑
tributes to distinct epidemiological patterns
rP
(reviewed in [1,2]). These two HIV types appear
to have been introduced into the human popula‑
tion via multiple interspecies transmissions from
simian immunodeficiency virus in chimpanzees
(HIV‑1) and sooty mangabeys (HIV‑2) [3] . While
ho
ro
& Matthew Cotten1
viruses overlaps. Due to cross-reacting antibodies 1
Medical Research Council (UK)
between HIV‑1 and HIV‑2, correct determina‑ Laboratories, Atlantic Road,
PO Box 273, Fajara, The Gambia
tion of actual HIV-D infection poses difficulty. 2
MRC/UCL Center for Medical
Initially, monospecific ELISAs or those detecting
Molecular Virology, Division of
both HIV‑1 and HIV‑2 antibodies were used to Infection and Immunity, University
College London, London, UK
screen patient samples, followed by a confirma‑ 3
Weatherall Institute of Molecular
tory western blot. However, cross-reactivity was Medicine, Medical Research Council
Human Immunology Unit, John
still observed in monospecific ELISAs [8] and Radcliffe Hospital, Oxford, UK
western blots [9–12] . Dual seropositivity with †
Author for correspondence:
Tel.: +220 449 5442

HIV‑2 infection in the majority of cases results
in long-term nonprogression, some individuals
go on to develop an AIDS-defining illness indis‑
tinguishable from that seen in HIV‑1 infection
[4] . Dual infection with both HIV‑1 and HIV‑2
was first suspected based on serological reactivity
ut
PCR confirmation has been used as the gold Fax: +220 449 5919
standard [13] . The sensitivity of PCR to detect tdesilva@mrc.gm
virus in singly HIV‑2-infected [14,15] and HIV-D-
infected [16,17] individuals has increased and can
reach up to 98% in HIV‑2 monoinfections and
72–85% in HIV-D infections. The specificity of

early in the epidemic [5] and confirmed by coiso‑
lation and PCR in 1988 [6,7] . Dual HIV‑1 and
HIV‑2 infection poses several important ques‑
tions: for example, does synergy between the two
A
synthetic peptide-based assays has also improved
and these are now widely used in rapid tests (the
recommended method of diagnosis in resource-
limited settings by the WHO and CDC). There

viruses result in a worse outcome for the infected
individual (and a greater therapeutic challenge),
or do inhibitory mechanisms and immune
responses exist that attenuate the course of either
infection? We review the published literature on
HIV‑1/2 dual (HIV-D) infection, focusing on
specific epidemiological and mechanistic topics
that arise with such a double infection. We also
consider the evidence for cross-reactive immune
responses, which may be relevant in the field
of HIV‑1 vaccine design. Finally, we detail the
problems of t­reating dual-infected patients.
Diagnosis of HIV‑1/2 dual infection
HIV-1/2 dual (HIV-D) infections are observed
in areas where the infection prevalence of the two
is a high concordance between these rapid tests
and real-time PCR methods for the detection of
dual infections, but false-positive diagnoses do
still occur [18] . Since both plasma and pro-viral
HIV‑2 loads can be very low in HIV-D-infected
individuals [19–22] , and primers may not always
detect a particular group of HIV‑2, PCR negativ‑
ity does not fully exclude the presence of HIV‑2.
Therefore, dual seroreactivity is highly suggestive
of dual infection but a sensitive method or algo‑
rithm for confirmation is required. This should
include sensitive and specific PCR test or a vali‑
dated testing algorithm including type-specific
antibody responses that are previously well vali‑
dated with PCR detection of both proviruses.
This is particularly important in diagnosing

10.2217/HIV.10.26 © 2010 Future Medicine Ltd HIV Ther. (2010) 4(3), xxx–xxx ISSN 1758-4310 1
Review | de Silva, van Tienen, Rowland-Jones & Cotten
HIV-D patients requiring antiretroviral therapy
(ART), as key differences in drug susceptibility
exist between HIV‑1 and HIV‑2 (see below).
Epidemiology of HIV‑1/2 dual infection
HIV‑1 and HIV‑2 show very distinct epidemi‑
ology; while HIV‑1 has spread globally and an
estimated 30 million people are infected in 2007
[201] , HIV‑2 has been confined to West Africa and
countries with socioeconomic links to Portugal
(reviewed in [23]). The first cases of HIV‑2 were
described in people from West Africa [24–26] and
further epidemiological studies confirmed that
this region has the highest infection rates. The
surprisingly high HIV‑2 prevalence in areas of
of
Guinea-Bissau has led to the suggestion that this
may represent a potential nucleus of the HIV‑2
epidemic (reviewed in [27]). In the late 1980s,
HIV‑2 prevalence was 8–10% in the adult pop‑
ro
ulation with over 15% infection in older indi‑
viduals, in both urban [28] and rural [29] areas.
Increased sexual risk behavior during the war
of independence (1963–1974) and iatrogenic
spread may have been factors that enhanced the
rP
epidemic in Guinea-Bissau [27,30–32] . Emigration
from West Africa to Europe accounts for the
great majority of HIV‑2 infections observed in
Europe [33] , particularly in countries with links to
West Africa such as Portugal, France and the UK
ho
[34–37] . The prevalence and incidence of HIV‑2
generally peaks in older individuals, as opposed
to HIV‑1, for which incidence and prevalence
(prior to large-scale ART) are higher in younger
individuals [38] .
HIV-1/2 dual infections in West-African
ut
countries are relatively common (Table 1) . HIV‑2
prevalence peaked in the early 1980s and sub‑
sequently declined, while HIV‑1 prevalence
increased and surpassed HIV‑2 prevalence in
A
most countries. HIV-D prevalence depends on
the prevalence of HIV‑1 and HIV‑2 and if both
infections are transmitted independently, the
highest HIV-D prevalence should be observed
when the prevalence of both viruses are high
([prevalence of HIV‑1] × [prevalence of HIV‑2] =
prevalence of HIV-D). A second important phe‑
nomenon may be relevant. Because of the high
frequency of long-term nonprogression in HIV‑2
infection and the low associated mortality, the
chances of an HIV‑2-infected subject acquiring
a second HIV infection is increased, especially as
HIV‑1 prevalence increases locally. For example,
in Guinea-Bissau in the late 1980s the HIV-D
prevalence was very low, then increased in the
1990s with the rise in HIV‑1 prevalence and
2 HIV Ther. (2010) 4(3)
subsequently declined, at the same time as HIV‑2
prevalence decreased [29,39–44] . The highest prev‑
alence of HIV-D has been reported in clinical
patients and commercial sex workers (38% in
1992) in Côte d’Ivoire, where HIV‑1 prevalence
was much higher than HIV‑2 prevalence. This
could be attributed to the high-risk nature of
these populations, but cross-reactivity in serolog‑
ical tests leading to an apparent but falsely high
HIV-D prevalence should also be considered. See
Figure 1 for an example of HIV‑1, HIV‑2 and
HIV-D trends over time in different countries
and population groups. It should be noted that
the method of diagnosis for each report included
in Table 1 and Figure 1 needs to be taken into
account and the prevalence of HIV-D inter‑
preted with caution in some cases (see section
on diagnosis of HIV‑1/2 dual infection above).
Two studies outside of West Africa have also
described a high HIV-D prevalence; HIV-D
prevalence among pregnant women in Zimbabwe
was reported to be 7.6% in 1994–1995 [45] and (a
surprisingly low) 0.9% in 1997–1999 [46] , while
there were no HIV‑2 monoinfections in the first
study and only one in the second. As the criteria
for diagnosing HIV-D infection were unclear [45]
and only these two studies from Zimbabwe have
reported on HIV-D or HIV‑2 monoinfections,
it is possible that cross-reacting antibodies were
responsible for HIV-D prevalence of 7.5% in
1994–1995. Other studies from Zimbabwe have
investigated overall HIV prevalence without dis‑
tinguishing between HIV‑1 and HIV‑2 [47–49] .
HIV-D cases have also been reported from dif‑
ferent regions in India and HIV‑2 may have
spread there via the Portuguese in colonial times
[50] . Most HIV-D cases reported from India in
the literature are from clinical patient groups
[51–53] . Some thought HIV‑2 would spread rap‑
idly in India [50,54] , but data from a hospital in
southern India showed a stable HIV‑2 prevalence
(2.5% of all HIV-positive cases) and an HIV-D
prevalence that declined from 0.8 to 0.4% (of
all HIV-positive cases) between 1993–1997 and
2000–2001 [55,56] .
Whether HIV‑2 more often precedes HIV‑1
or vice versa is not clear from the literature,
although an examination of incident HIV-D
cases in The Gambia suggests that the major‑
ity of dual-infected patients acquired HIV‑2
first before becoming superinfected with HIV‑1
[van  Tienen  C, de  Silva  TI, Unpublished Data] . The
prevalence and the different dates at which the
two viruses entered the local human popula‑
tion are likely to contribute to the sequence of
future science group
 Dual infection with HIV‑1 & HIV‑2: double trouble or destructive interference?
infection. In West Africa, HIV‑2 prevalence was
high in the 1980s and subsequently declined,
while HIV‑1 increased in the 1990s and there‑
fore HIV‑2 would more often be the first virus
acquired. However, it has also been argued that
HIV‑2 is acquired later in life because of the low
transmissibility and therefore HIV‑1 would more
often precede HIV‑2 infection [57] . The low prev‑
alence of HIV‑2 monoinfection and the much
higher HIV-D prevalence in Côte d’Ivoire may
exemplify this [58–60] . However, in most countries
HIV-D prevalence is lower than the HIV‑2 prev‑
alence (Table 1) . Studies have generally focused
on HIV‑1 incident infection in HIV‑2-infected
individuals and not the other way around. Also,
| Review
would have died more rapidly than HIV‑2-
infected individuals and sampling may not have
been frequent enough in cohorts to study the
incident HIV‑2 cases in those previously HIV‑1
monoinfected. Thus, although HIV‑2 precedes
HIV‑1 superinfection in general rather than the
other way round, it is premature to conclude
that the rarity of HIV‑2 superinfection on an
HIV‑1 background is a result of some degree of
cross-protection.
Prevalence of different HIV‑1 & HIV‑2
subtypes in HIV‑1/2 dual infection
A few studies have explored the hypothesis that
particular subtypes of HIV‑1 and HIV‑2 may

of
in the pre-ART era, HIV‑1-infected individuals be more frequently found in HIV-D-infected

Table 1. HIV-1/2 dual, HIV‑1 and HIV‑2 infection prevalence in adult populations in West Africa: cross-sectional
data between 1985 and 2007.
Country
Mali
Population
Students
Female CSWs
Period
2005
1987
1995 ro Persons (n) HIV dual (%)
950
NA
176
0.2
13
6.2
HIV‑1 (%) †
4.9
10
35.8
HIV‑2 (%) †
0.2
15
3.9
Ref.
[144]
[145,146]
[146]
rP
Guinea-Bissau Pregnant women 1987–1997 11,371 0.2 0.9‡ 5.5‡ [40]
1997 1491 0.5 2.0 4.6 [39]
1999–2001 4505 0.8 3.9 3.5 [39]
2002–2004 4503 0.4 4.5 1.9 [39]
Police officers 1990–1996 2637 0.5 0.9 9.7 [40]
ho

1996–1998 552 1.4 2.2 6.3 [147]

2003–2004 1238 1.2 8.3 4.9 [147]
2005–2007 548 1.5 5.8 4.7 [147]
Adults (rural area) 1989–1991 2770 0.4 0.1 7.9 [29,41]
1996–1998 3110 0.9 1.6 6.8 [29,41]
2006–2007 2895 0.7 2.9 4.0 [29,41]
ut

Adults (urban area) 1987 603 0.2 0 8.9 [42]

1995–1996 1505 0.9 1.3 5.9 [43]
2004–2007 2548 0.4 4.2 3.9 [44]
A

The Gambia Pregnant women 1993–1995 29,549 0.1 0.5 1.1 [148]
2000–2001 8054 0.2 1.2 0.8 [149]
Female CSWs 1988 355 1.1 0.6 24.5 [150]
1989 241 2.5 2.1 26.1 [150]
1990–1991 104 1.9 5.8 13.5 [151]
1992–1993 207 5.8 8.2 21.7 [152]
STD patients 1983–1984 117 0 0 0 [153]
1986 185 0 0 5.4 [153]
1988–1990 443 0 0.1 4.7 [154]
Genito-urinary 1988–1991 3775 0.8 4.2 7.0 [155]
medicine clinic 1992–1994 3807 0.9 8.0 7.4 [155]
1995–1997 4609 1.1 10.6 6.3 [155]
1998–2000 5669 1.2 14.5 5.3 [155]
2001–2003 5503 0.9 17.5 4.0 [155]
†
The HIV-1/2 dual infections were excluded from the HIV‑1 and HIV‑2 single infections unless indicated otherwise.
‡
Not stated in paper whether HIV-1/2 dual infections are excluded from the HIV‑1 and HIV‑2 single-infection figures.
CSW: Commercial sex worker; STD: Sexually transmitted disease.

future science group www.futuremedicine.com 3

Review | de Silva, van Tienen, Rowland-Jones & Cotten

Table 1. HIV-1/2 dual, HIV‑1 and HIV‑2 infection prevalence in adult populations in West Africa: cross-sectional
data between 1985 and 2007.
Country Population Period Persons (n) HIV dual (%) HIV‑1 (%) † HIV‑2 (%) † Ref.
Côte d’Ivoire Pregnant women 1987 200 1 7 2 [58]
1988 537 3 5 1 [58]
1990 3153 1 9 2 [58]
1991 10,134 1 10 1 [58]
1992 5363 1 9 2 [58]
2001–2002 1039 0.2 10.6 0.5 [18]
Adults with TB 1987 200 8 16 4 [58]
1989 1994 10 28 5 [58]
1990 3843 9 32 4 [58]
1991 3495 8 35 4 [58]
1992 3736 9 35 3 [58]

of
1993 3380 9 35 3 [58]
Infectious disease 1987 114 17 27 7 [58]
ward 1988 752 14 30 5 [58]
1990 3123 13 43 4 [58]

ro
1991 2225 11 45 4 [58]
1992 720 16.5 53 2.5 [58]
Pulmonary medicine 1986 1987 2 15 2 [58]
ward 1988 179 14 33 3 [58]
rP
1989 473 14 38 4 [58]
1990 426 16 44 3 [58]
1991 686 12 49 4 [58]
1992 291 13 54 3 [58]
Internal medicine ward 1988 316 4 14 5 [58]
1991 1872 5 21 3 [58]
ho

Dermatology patients 1988 86 13 27 3.5 [58]

1992 57 15 28 3 [58]
Female CSWs 1996–1997 343 14 44 1 [60]
1992 356 38 49 3 [59]
1993 778 30 47 2 [59]
ut

1994 607 23 43 2 [59]

1995 832 14 37 2 [59]
1996 916 12 39 1 [59]
1997 876 9 40 2 [59]
A

1998 853 3 29 1 [59]

Senegal Female CSWs (Dakar, 1990–1993 759 2 9 8 [156]
Thies, Mbour)
Female CSWs (Dakar) 1985–1990 1275 0.7 4.1 10.0 [157]
Female CSWs 1987–1990 278 0 0.4 38.1 [157]
(Ziguinchor)
Female CSWs 1987–1990 157 0 1.3 27.4 [157]
(Kaolack)
Female CSWs (Dakar) 1985–1993 1452 0.8 6.2 11.3 [157]
Adults rural area 1990 3230 0 0.1‡ 0.8‡ [158]
1995 2179 0 0.3‡ 0.6‡ [158]
Ghana Outpatients 1999 854 0.6 8.3‡ 0.9‡ [159]
†
The HIV-1/2 dual infections were excluded from the HIV‑1 and HIV‑2 single infections unless indicated otherwise.
‡
Not stated in paper whether HIV-1/2 dual infections are excluded from the HIV‑1 and HIV‑2 single-infection figures.
CSW: Commercial sex worker; STD: Sexually transmitted disease.

4 HIV Ther. (2010) 4(3) future science group

 Dual infection with HIV‑1 & HIV‑2: double trouble or destructive interference?
individuals, although it is not clear what biologi‑
cal mechanisms would promote such an associa‑
tion [61–64] . Common wisdom would suggest that
simple infection numbers dominate the probabil‑
ity of coinfection. Thus, any apparent associa‑
tion of a particular HIV‑1 or HIV‑2 genotype
with HIV-D infection is probably largely limited
by the combined frequency of exposure to the
particular genotypes rather than to any specific
molecular features of a genotype. Nonetheless,
there is a report that a variant of HIV‑1 sub‑
type  A (A3 [65,66]) is preferentially found in
| Review
HIV-D infections [61] . The researchers suggest
that a potential protective effect of HIV‑2 on
HIV‑1 acquisition, which is disputed, is ­somehow
weaker for this particular HIV‑1 variant [61] .
Studies in Guinea-Bissau found a predomi‑
nance of CRF02_AG-like viruses in HIV‑1
monoinfections and no enrichment of any other
HIV‑1 type in the HIV-D infections exam‑
ined  [62] . In a study from a Ghanaian cohort,
variation in the envelope V3 region was exam‑
ined. This region is the most variable segment
of the HIV genome and a good place to identify

20 60

of
Prevalence (%)

Prevalence (%)
15
40
10

20

ro
5

0
0
1

3
99

99

99

00

00

87

88

90

91

92
–1

–1

–1

–2

–2

19

19

19

19

19
rP
88

92

95

98

01

Infectious disease ward patients,

19

19

19

19

20

GUM clinic outpatients, The Gambia Côte d’Ivore

10 10
Prevalence (%)

Prevalence (%)
ho

5 5

0 0
ut

1
7

97

01

04

99

00
99

19

20

20

–1

–2
–1

93

00
87

99

02

19

20
19

19

20

Pregnant women, Guinea-Bissau Pregnant women,

The Gambia
A

10
Prevalence (%)

HIV-D HIV-1 HIV-2

5

0
87

88

90

91

92

2
00
19

19

19

19

19

–2
01

Pregnant women, Côte d’Ivore

20

Figure 1. Prevalence of HIV‑1/2 dual, HIV‑1 and HIV‑2 infections over time in different
patient populations. (A) GUM clinic outpatients from The Gambia [153] . (B) Infectious disease ward
inpatients from Côte d’Ivoire [58] . (C) Pregnant women from Guinea-Bissau [39,40] , The Gambia
[148,149] and Côte d’Ivoire [58] .
GUM: Genitourinary medicine; HIV-D: HIV‑1/2-dual infection.

future science group www.futuremedicine.com 5

Review | de Silva, van Tienen, Rowland-Jones & Cotten
distinctive variants. No preferential associa‑
tion of V3 variants was observed in dual versus
monoinfections [63] . Two studies from Dakar
have also failed to find significant differences in
the HIV‑1 and HIV‑2 subtypes of dual versus
monoinfections [64,67] . Because of the limited
geography of HIV-D infection and the limited
number of studies of this phenomenon, it is not
surprising that limited HIV sequence data are
available from these patients. However, in the
available data, there is no strong support for spe‑
cific HIV‑1 or HIV‑2 variants that are associated
with coinfection.
Potential for forming HIV‑1
& HIV‑2 recombinants
of
Interest in this idea is most likely fuelled by the
concern that two lethal viruses coinfecting the
same host might recombine and produce an
ro
even more aggressive pathogen. There are sev‑
eral essential steps required for recombination
between HIV‑1 and HIV‑2. The patient must
be dual infected and both types of virus must be
present in the same cell. It is easy to understand
rP
how dual infection can occur in the same host;
however, dual infection of the same cell might
be less likely to occur. Classical retrovirology
teaches us that retroviruses have mechanisms
to downregulate their receptors upon infection.
ho
This is essential to prevent envelope protein
interaction with receptors during virus produc‑
tion and egress, which can interfere with effi‑
cient virus assembly. This mechanism also pre‑
vents superinfection by viruses using the same
receptors. Since both HIV‑1 and HIV‑2 have
ut
these functions, superinfection of an HIV‑2-
infected cell by HIV‑1 (or vice versa) is strongly
discouraged [68] . However, at least 45 different
circulating recombinant forms of HIV‑1 have
A
been described, indicating that this barrier to
cocellular infection is not as strict in vivo [202] .
If both HIV‑1 and HIV‑2 do somehow infect
the same cells within a dual-infected patient,
recombination between the two viral genomes
would require several additional molecular
events. Recombination is greatly enhanced in
HIV due to the packaging of two copies of the
RNA genomes in a single virion. This facilitates
the strand transfer occurring during reverse
transcription, which drives retroviral recombi‑
nation. RNA genome dimer formation requires
a sequence element called the dimer initiation
site (DIS) found near the 5´-end of each mol‑
ecule. Detailed examination of the DIS ele‑
ment has revealed both sequence and structural
6 HIV Ther. (2010) 4(3)
differences that interfere with the formation of
HIV‑1–HIV‑2 dimers [69] . The incompatibil‑
ity between HIV‑1 and HIV‑2 DIS elements
impairs copackaging of the two genomes and
would be a major block to the formation of
HIV‑1–HIV‑2 recombinants. The importance
of the DIS in recombination is supported by the
observation that even within different HIV‑1
subtypes, the lack of a homologous DIS pres‑
ents a strong barrier to recombination, at least
in in vitro systems [70–72] . Although there is a
suggestion that HIV‑1 recombinants are more
frequent between subtypes with identical DIS
elements [69] , the significant number of observed
recombinants between those with different DIS
elements (e.g., AB, BC or BF recombinants) sug‑
gests additional factors may positively influence
recombination in vivo.
If an HIV‑1–HIV‑2 RNA genome dimer
did happen to form and be packaged (against
all of these odds), the next step in recombina‑
tion, namely strand transfer occurring during
reverse transcription, is unlikely to be limiting.
The HIV‑2 strand transfer frequency is simi‑
lar to HIV‑1 (perhaps slightly higher). This is
consistent with recent evidence that at least
one HIV‑2 intergroup recombinant exists and
may be circulating  [73,74] . Beautifully designed
experiments using genetically marked genomes
measured a high strand-transfer rate of nearly
four events per genome per replication cycle
for both HIV‑1 and HIV‑2, suggesting that
strand transfer is an integral part of HIV rep‑
lication  [75] . Thus, in the highly unlikely event
that HIV‑1 and HIV‑2 genomes locate in the
same cell and are copackaged within the same
virion, it is likely that strand transfer to form a
recombinant could occur.
Despite all of these barriers to HIV-1–HIV‑2
recombinant formation, it still interests research‑
ers to ask: if all of the conditions are optimized
to overcome these barriers and favor coinfection,
can the two viruses recombine? Using an alter‑
nate assay type, HIV‑1–HIV‑2 recombination has
been demonstrated to occur in cell culture [76] , in
which the presence of both viral genomes within
the same host cell can be ensured. Cells were
coinfected with recombinant HIV‑1 and HIV‑2,
each bearing a differently mutated green fluores‑
cent protein (GFP) cassette. Recombinants were
identified by cells expressing GFP fluorescence,
restored when a recombination event corrected
the mutations in a single GFP cassette. In this
system, HIV‑1–HIV‑2 recombination was found
to occur in approximately 0.2% of the infection
future science group
 Dual infection with HIV‑1 & HIV‑2: double trouble or destructive interference?
events, approximately 35-fold less frequently
than HIV‑1/HIV‑1 recombination occurs in
the same system.
Gag proteins from both viruses can coas‑
semble within the same virion [77] , suggesting
a conserved function and conserved interaction
with other virion proteins. Such complemen‑
tation is not uniformly reciprocal: HIV‑1 can
package HIV‑2 genomes; however, HIV‑2 is not
able to package HIV‑1 genomes [78] . Replacing
the HIV‑2 Gag p2 and nucleocapsid regions with
those of HIV‑1 allows HIV‑1 genome packaging
by HIV‑2 [78] .
Although the number of studies investigat‑
ing these issues is limited, there is currently
no genetic evidence of recombination having
occurred between HIV‑1 and HIV‑2 in natural
infection. An examination of 46 HIV-D patients
was performed using a sensitive PCR assay to
detect potential recombination events in the
envelope region [79] . No recombinants from this
region were identified. Curiously, less than 50%
of the subjects yielded both HIV‑1 and HIV‑2
PCR products, suggesting either that the PCR
rP
conditions may not have been optimum for the
local sequences (a common problem) or that the
dual infections were falsely diagnosed [79] . There
is still the possibility that an HIV‑1/2 recom‑
binant might be identified if a broader set of
ho
PCR primers tuned to the local sequence variety
is used, if a larger number of HIV-D patients
are examined or if other possible recombination
sites within the viruses are examined. However
the bulk of the data on this topic support the
conclusion that there are strong viral barriers to
ut
HIV‑1–HIV‑2 recombination and there is no
clinical evidence of the event.
HIV‑2 protection against
A
incident HIV‑1 infection:
epidemiological studies
In a high-profile article by Travers et al. in 1995,
a lower incidence of HIV‑1 among HIV‑2-
infected women than among HIV-uninfected
women was reported (adjusted incidence rate
ratio [IRR]: 0.32), suggesting a protective effect
of 68% [80] . It was thought that a potential selec‑
tion bias had occurred in this study [81] , but a
reana­lysis using all available data still showed
a protective effect of 64% [82] . After this study,
different West African groups analyzed their
own longitudinal data derived from indepen‑
dent cohorts for a similar protective effect. Six
subsequent studies all showed an increased IRR,
ranging from nonsignificantly increased IRRs
future science group
| Review
(1.6–2.7) [40,83,84] to significantly increased
IRRs (9.4–19.8) [85,86] . A weighted average of
all studies on this topic gave an estimated IRR
of 2.5 (95%  CI:  1.8–3.5)  [87] . Collectively,
these results indicate that HIV‑2 does not pro‑
tect against HIV‑1 infection and may actu‑
ally be a risk factor. It is not known whether
this increased risk of incident HIV‑1 infection
would be explained by risky sexual behavior or
an increased biological susceptibility.
Cross-reactive immune responses in
HIV‑1, HIV‑2 & HIV‑1/2 dual infection
While epidemiological studies strove to clarify
initial claims from Travers et al. [88] , the potential
of
mechanisms behind this observation relevant to
HIV‑1 vaccine design were sought. Strong HIV-
specific responses in HIV‑2-infected donors that
exhibit cross-reactivity against HIV‑1 have been
ro
reported, including polyfunctional T-helper and
cytotoxic T lymphocyte (CTL) responses [89–91] .
Although cross-clade CTL reactivity may have
been over-reported in HIV‑1 infection owing to
the use of synthetic peptides at artificially high
concentrations, at least some of these experiments
show that T‑cell responses from HIV‑2-infected
donors recognize cells infected with vaccinia
virus constructs expressing the relevant HIV‑1
antigen, suggesting that cross-reactivity extends
to naturally processed antigens for some HLA
alleles, particularly HLA-B35 [91] and B58 [90] . In
Bertoletti’s study, polyclonal CTL from nine of
11 HIV‑2-infected donors showed cross-reactiv‑
ity towards naturally processed HIV‑1 Gag pep‑
tides, with five donors recognizing cells infected
with recombinant vaccinia viruses from three
or more different HIV‑1 clades [90] . This may
reflect the greater polyclonality of T‑cell receptor
usage described in HIV‑2 infection [92] . In other
cases, such as B53 [93] and B27 [94] alleles, no
cross-reactivity from HIV‑2-specific CTL could
be detected. This raises the possibility that, if
T cells play a role in protection against super­
infection, cross-protection may be seen in donors
with specific HLA types and not others (which
could explain the very specific results observed
in only the one cohort of Dakar sex workers and
not in any other West African cohort): this has
not to date been formally investigated and with
the falling prevalence of HIV‑2 infection across
West Africa becomes increasingly hard to study.
For both HIV‑1 and HIV‑2 infection, there
is a link between T‑cell responses, both CD4 +
[95,96] and CD8 + [97,98] , directed towards Gag, and
low viral load (VL), although this relationship
www.futuremedicine.com 7
Review | de Silva, van Tienen, Rowland-Jones & Cotten
is much clearer for HIV‑2, where there is a sig‑
nificant inverse correlation between HIV‑2
VL and responses to a highly conserved epit‑
ope in the major homology region of Gag p26
[98] . Furthermore, polyfunctional CD4 + T‑cell
responses to HIV‑1 are relatively rare compared
with those seen in HIV‑2 infection [95] . There have
been few studies of cellular immune responses
in dual-infected subjects, either before or after
HIV‑2 superinfection: cellular immune responses
may depend on the relative replication of the
two viruses after coinfection with corresponding
T‑cell stimulation. The pattern of viral replication
in HIV-D patients varies significantly between
individuals and cannot easily be predicted. T‑cell
of
responses against HIV‑2 Gag correlate inversely
with HIV‑1 VL in HIV-D-infected individu‑
als and higher frequencies of IFN‑g-secreting
HIV‑1 specific CD4 + T cells are seen in HIV-D
ro
patients when compared with those with HIV‑1
monoinfection [99,100] . These data are consistent
with the potential for viral control of strong T‑cell
responses to regions of the Gag protein that are
conserved between the two viral strains.
rP
Although Gag and Pol enzymes show greater
conservation (~60%) than Env proteins (~40%)
between HIV‑1 and HIV‑2 [101–103] , there are
also reports of modest cross-neutralization
of HIV‑1 by HIV‑2 sera [104–106] . The high‑
ho
est breadth of cross-neutralization, however,
is only seen against neutralization-sensitive
laboratory strains SF-2 [106] and NL4-3 [105] .
The most recent study, using a pseudovirus
reporter neutralization assay, found only 38%
of HIV‑2 patients showed any cross-neutraliza‑
ut
tion of primary HIV‑1 envelopes (and with low
magnitude neutralization titers) [105] . It is an
attractive hypothesis with relevance to HIV‑1
vaccine development that in some individuals,
A
cross-neutralizing antibody responses elicited
by HIV‑2 infection may protect against HIV‑1
superinfection. Data from the macaque model
suggests that time from HIV‑2 seroconversion
may be relevant, where susceptibility to super‑
infection with HIV‑1 in HIV‑2-infected animals
reduced over time [107] . A case report of HIV‑1
superinfection with subsequent low HIV‑1 VL
set point and viremic control, in a chronically
HIV‑2-infected woman, failed to detect HIV‑1
cross-neutralizing antibodies, suggesting that
other mechanisms were responsible for the
benign course of HIV‑1 disease observed [108] .
A study of macaques immunized with attenuated
poxvirus recombinants expressing either HIV‑1
or HIV‑2 proteins (followed by homologous
8 HIV Ther. (2010) 4(3)
oligomeric gp160 boosts) and challenged with
SHIV HXB2 or HIV‑2SBL666 explored the extent of
cross-protection and underlying immunologi‑
cal responses [109] . A degree of cross-protection
was observed following HIV‑1 immuniza‑
tion and HIV‑2 challenge, but not vice versa,
despite the development of cross-reactive CTL
responses (but not cross-neutralizing antibodies)
in HIV‑2-immunized macaques. The potential
for cross-reactive antibodies or T cells to protect
against superinfection in HIV‑2 singly-infected
subjects subsequently exposed to HIV‑1 infec‑
tion has not been formally tested, although
this could potentially provide valuable proof-
of-concept data about correlates of protective
­immunity for HIV vaccine strategies.
If indeed protection against HIV‑1 infec‑
tion by HIV‑2 infections occurs under some
specific conditions, several mechanisms other
than cross-reactive adaptive immune responses
have been proposed to account for this. HIV‑2
may inhibit HIV‑1 replication at the molecular
level, possibly involving intracellular competi‑
tion between viruses for a limiting transcrip‑
tional factor [110] or by influencing the assembly
or release of HIV‑1 [111] . However, it is difficult
to imagine how a large proportion of potential
HIV‑1 target cells in a patient might be occupied
by HIV‑2, which would be required if either of
the above mechanisms were relevant in vivo. A
more plausible mechanism would be one that
functions cellularly in trans, that is, HIV‑2-
infected cells may change the entire environment
to alter the susceptibility of noninfected cells to
HIV‑1. Such a mechanism has been described in
peripheral blood mononuclear cells from HIV‑2-
infected patients, which show resistance to
in vitro challenge with HIV‑1 isolates relative to
HIV-uninfected peripheral blood mononuclear
cells; an effect possibly mediated via increased
b-chemokine secretion [112] .
Disease progression & VL dynamics in
HIV-D patients
The weight of current epidemiological evidence
challenges the view that HIV‑2 infection confers
absolute protection against subsequent HIV‑1
infection. Yet it is possible that the presence of
cross-reactive immune responses due to prior
HIV‑2 infection may alter the subsequent course
of HIV‑1 infection in HIV-D-infected individ‑
uals. Some support for this is provided by the
observation that although chronically HIV‑2-
infected macaques are not resistant to challenge
with pathogenic SHIV89.6p, they are relatively
future science group
 Dual infection with HIV‑1 & HIV‑2: double trouble or destructive interference?
protected from subsequent CD4 + T‑cell deple‑
tion in comparison to seronegative controls
infected with the same SHIV strains [113] . Study
of HIV‑1 and HIV‑2 VLs in HIV-D-infected
subjects also offers the unique opportunity of
observing in vivo viral dynamics between two
potentially pathogenic retroviruses, with the pos‑
sibility that competition and/or synergy between
the two may occur to the benefit or detriment of
the infected host.
An early study of HIV-infected pregnant
women from Côte d’Ivoire found CD8 + T‑cell
numbers, CD4:CD8 ratios and serum IgG levels
to be similarly aberrant in HIV‑1- and HIV-D-
infected individuals when compared with HIV‑2
monoinfected and uninfected women  [114] .
Although it is worth noting the population used
were symptomatic HIV-infected patients from
TB treatment centers (also in Côte d’Ivoire), the
first study of mortality in 243 dual-seropositive
patients found mortality rates to be equally
high in HIV‑1 and HIV-D over 2 years, with
lower mortality rates seen in HIV‑2-infected
and HIV-uninfected individuals  [115] . Several
rP
subsequent studies, from several populations,
have also compared mortality in HIV-D-
infected individuals with those mono­infected
with HIV‑1 or HIV‑2 (summarized in Table 2).
Although only one of these was a community
ho
cohort study [116] (and therefore a better popula‑
tion to study the natural history of HIV-D than
clinic or hospitalized patients), all of these stud‑
ies have rejected the hypothesis that survival is
better in HIV-D when compared with HIV‑1.
Evidence to date suggests that HIV-D-related
ut
mortality is dependent on CD4 + T‑cell count, is
equivalent to that in HIV‑1 monoinfection and
is higher than in HIV‑2 monoinfected individu‑
als matched for disease stage [19,116–118] . A further
A
community cohort survival ana­lysis including
a greater number of HIV-D-infected individu‑
als, ideally with a proportion with documented
HIV‑2 to HIV-D seroconversion, would further
strengthen this conclusion.
A small study from Guinea-Bissau sug‑
gested that HIV‑1 plasma VL (PVL) was sig‑
nificantly lower in HIV-D-infected individuals
than in those monoinfected with HIV‑1 [119] .
Apart from the limited number of patients in
this study, a further clear confounding factor
is that HIV‑1 seroprevalent individuals were at
a more advanced disease stage when compared
with HIV-D-infected individuals (mean CD4 +
T‑cell count: 80 vs 295 cells/mm3). Several stud‑
ies since have refuted this initial observation.
future science group
| Review
Equivalent HIV‑1 PVL in HIV‑1-monoinfected
and HIV‑D-infected individuals have been
demon­strated in genitourinary medicine clinic
attendees in The Gambia [19] , as well as female
commercial sex workers, HIV outpatient clinic
attendees and pregnant women from Côte
d’Ivoire [20,60] . Although the cross-sectional study
design, use of symptomatic clinic populations
and the lack of a known HIV-D seroconversion
date (or sequence of HIV‑2 and HIV‑1 infec‑
tion) are potential criticisms, two of these studies
matched patients by CD4 + T‑cell count strata,
demonstrating the same effect at each disease
stage [19,60] . Finally, as mentioned above, CTL
responses cross-reactive for HIV‑1 have been
of
identified in HIV‑2 patients with B35, B53 and
B58 alleles [90,91,120] . However, the presence of
these alleles in HIV-D-infected patients only has
a weak effect on HIV‑1 replication [19] . The cur‑
ro
rently available evidence from PVL measurement
therefore further rejects the idea that the pres‑
ence of HIV‑2 favorably modulates the course of
HIV‑1 infection in HIV-D-infected individuals.
By contrast, an effect of HIV‑1 coinfection
on in vivo HIV‑2 viral dynamics is apparent. At
advanced stages of immunosuppression (CD4
<14% or <200 cells/mm3), HIV‑2 PVL in HIV-
D-infected patients is significantly lower than in
HIV‑2-monoinfected subjects matched for dis‑
ease stage [19,20] . These observations in circulat‑
ing virus levels are also mirrored in HIV‑2 proVL
assessments in HIV‑2 and HIV-D patients [22] .
The likelihood of a detectable HIV‑2 PVL,
proVL and DNA positivity (with nested PCR)
are all significantly reduced in HIV-D-infected
individuals with increasing disease progression
[19–22] . Furthermore, in HIV‑2 monoinfection,
an inverse relationship between CD4 + T‑cell
count and both HIV‑2 proVL and PVL is usu‑
ally observed (as with HIV‑1 PVL in HIV-D
and HIV‑1 monoinfection), whereas this pat‑
tern appears to be lost in HIV-D-infected indi‑
viduals, with HIV‑2 PVLs found to be similar
across all CD4 + T‑cell strata [19] and a paradoxi‑
cal positive correlation is observed with HIV‑2
proVL and CD4 + T‑cell count [21] . Intriguingly,
both HIV‑2 PVL and proVL in subjects with
preserved CD4 + T‑cell counts and asymptom‑
atic infection appears to be higher in HIV-D
infection than in HIV‑2 monoinfection. The
reasons for this observation are not clear, but
could be a result of higher generalized immune
activation in HIV-D-infected individuals (sec‑
ondary to HIV‑1 coinfection) leading to a more
favorable cellular environment for HIV‑2 viral
www.futuremedicine.com 9
10
Table 2. Summary of studies comparing risk of mortality in HIV‑1/2 dual-, HIV‑1- and HIV‑2-infected individuals.
Setting Diagnosis of HIV-D Follow-up period Subjects in study (n) Mortality rates† Ref.
status
TB treatment centers, ELISA with immuno- 6 months (all those initiating TB Initiated TB therapy: Hazard ratio (95% CI) relative to HIV uninfected [115]
Cote d’Ivoire enzymatic strip/western therapy) HIV uninfected: 282 controls at:
blot confirmation 2 years (all those completing TB HIV‑1: 167 6 months (all those initiating TB therapy):
therapy) HIV‑2: 143 HIV‑1: 6.5 (2.1–19.5)
HIV-D: 243 HIV‑2: 3.0 (0.8–10.6)
Completed TB therapy: HIV-D: 10.8 (3.8–30.3)
HIV uninfected: 222 2 years (all those completing TB therapy):
HIV‑1: 120 HIV‑1: 7.1 (2.9–17.3)
HIV‑2: 101 HIV‑2: 2.6 (0.9–7.6)
A HIV-D: 155 HIV-D: 8.2 (3.8–30.3)
Hospitalized patients ELISA and immuno- 8 months (treatment and FU period HIV uninfected: 74 MRR (95% CI) relative to HIV uninfected: [160]
with TB, enzymatic strip for TB). HIV‑1: 11 HIV‑1: 3.1 (0.7–14.3)
Guinea-Bissau HIV‑2: 30 HIV‑2: 4.3 (1.5–12.5)
HIV-D: 12 HIV-D: 5.7 (1.8–17.8)
Community TB ELISA and immuno- 8 months (treatment and FU period HIV uninfected: 222 MRR adjusted for age and sex (95% CI) relative [118]
ut
surveillance enzymatic strip for TB). HIV‑1: 41 to HIV uninfected:
programme, HIV‑2: 67 HIV‑1: 2.68 (1.11–6.48)
Guinea-Bissau HIV-D: 30 HIV‑2: 1.19 (0.46–3.06)
HIV-D: 2.89 (1.13–7.39)
ho
Genitourinary ELISA, immuno- Median FU (range): Mortality rate per 100 person-years (95% CI): [117]
Review | de Silva, van Tienen, Rowland-Jones & Cotten

medicine clinic, enzymatic strip, PCR HIV‑1, 10.6 months (0–117) HIV‑1: 746 HIV‑1: 35.3 (32.0–38.7)
The Gambia confirmation HIV‑2, 5.7 months (0–128) HIV‑2: 666 HIV‑2: 22.0 (19.7–24.3)
HIV-D, 8.6 months (0–106) HIV-D: 107 HIV-D: 41.7 (31.4–52.0)

HIV Ther. (2010) 4(3)

Genitourinary ELISA, immuno- Median FU (range): Hazard ratio (95% CI) of HIV‑1 relative to: [19]
medicine clinic, enzymatic strip, PCR HIV‑1, 2.4 years (0–8.5) HIV‑1: 119 HIV‑2: 1.41 (1.0–1.8)
rP
The Gambia confirmation HIV‑2, 3.8 years (0–8.7) HIV‑2: 137 HIV-D: 0.74 (0.6–1.1)
HIV-D, 1.5 years (0–6.1) HIV-D: 81 Hazard ratio (95% CI) of HIV-D relative to:
HIV‑2: 1.5 (1.1–2.2)
Urban community Not stated. Previous Median FU (range): HIV uninfected: 1421 Age-adjusted MRR (95% CI) relative to HIV [116,162]
survey, publications with same HIV‑1 men, 2.5 years (0.2–4.3) HIV‑1: 22 uninfected controls:
ro
Guinea-Bissau cohort used ELISA HIV‑1 women, 3.1 years (0.4–3.8) HIV‑2: 383 HIV‑1 men: 5.2 (1.9–14.0)
screening and HIV‑2 men, 3.8 years (0.2–11.6) HIV-D: 13 HIV‑1 women: 4.7 (1.5–14.6)
confirmation HIV‑2 women,3.7 years (0.1–12.0) HIV‑2 men: 1.6 (1.1–2.2)
HIV-D men, 3.2 years (0.3–5.9) HIV‑2 women: 2.1 (1.6–2.8)
HIV-D women, 2.6 years (0.6–4.5) HIV-D men: 4.3 (1.1–17.3)
HIV-D women: 7.9 (2.5–24.9)
of
†
All subjects included in these studies were antiretroviral therapy naive during the period of follow-up.
FU: Follow-up; HIV-D: HIV‑1/2 dual; MRR: Mortality rate ratio.

future science group

 Dual infection with HIV‑1 & HIV‑2: double trouble or destructive interference?
replication  [60] . It seems clear, therefore, that
in the majority of individuals coinfected with
HIV‑1 and HIV‑2, HIV‑1 outcompetes HIV‑2
over time and is the main driving force behind
disease progression. The observation that a
strong relationship between immune activation
(as measured by HLA-DR or CD38 expression
on CD8 + T  cells) and HIV‑2 PVL exists in
HIV‑2 monoinfected individuals, but not HIV-
D-infected individuals [20] , further suggests that
in HIV-D infection, HIV‑2 plays only a bit part
to HIV‑1’s lead role.
ART in HIV‑1/2
dual-infected individuals
The need to consider baseline antiretroviral sus‑
ceptibility and the development of resistance
mutations leading to virological failure, for both
HIV‑1 and HIV‑2, makes the management of
ART in HIV-D infections complex. Even in set‑
tings where VL testing is a possibility, the lack
of a standardized and well-validated HIV‑2 VL
assay that is commercially available also compli‑
cates the process of monitoring therapy. HIV‑2
rP
strains are naturally resistant to all currently
available non-nucleoside reverse transcriptase
inhibitors (NNRTIs) [121,122] and have reduced
susceptibility to some protease inhibitors (PIs)
successfully used in treating HIV‑1 [123] . Current
ho
evidence from in vitro studies suggests that lopi‑
navir (LPV), saquinavir (SQV) and darunavir
(DRV) are the most potent PIs against HIV‑2
and should be considered first-line choices along‑
side two appropriate nucleos(t)ide reverse tran‑
scriptase inhibitors (NRTIs) in treatment regimes
ut
for HIV‑2- and HIV-D-infected patients [124] ,
although the presence of background PI muta‑
tions in HIV‑2 may reduce the genetic barrier to
resistance to PIs such as LPV (when compared
A
with that in HIV‑1) and increase the chances
of virological failure [125] . Data on the efficacy
of tipranavir in HIV‑2 treatment is contrasting,
with some in vitro studies showing reasonable
potency [124] , whilst others have found relative
resistance when compared with LPV, SQV and
DRV [123,126] and several-fold lower susceptibility
than against HIV‑1 [126] . As previously outlined,
the majority of worldwide HIV-D infections are
found in West Africa, largely in resource-limited
settings where ART has become available only
in recent years. Combined with the relatively
low prevalence of HIV-D when compared with
HIV‑1 or HIV‑2, it is not surprising that there is
little evidence in the literature to guide treatment
of HIV-D-infected individuals. Confined mainly
future science group
| Review
to early case reports until recently, there are now
a few case series and observational cohort studies
reporting outcomes of HIV-D patients on ART
(summarized in Table 3). Even so, heterogene‑
ity in ART regimes used (including suboptimal
PI-based and inadvertent NNRTI-based regime
use) and lack of consistent VL monitoring in these
reports, as well as the absence of any randomized
controlled trials to date, leave unanswered ques‑
tions. There are still a few conclusions that can be
drawn by examining the available data.
Case reports of two HIV-D-infected indi‑
viduals treated with SQV/ritonavir (SQV/r)
alone in one and zidovudine (AZT), lamuvi‑
dine (3TC) and nelfinavir in the other, showed
of
HIV‑1 VL suppression but a poor response in
HIV‑2 VL,providing the first warning that usual
regime choices for HIV‑1 may not be adequate in
HIV-D patients [127] . A further case report also
ro
showed poor HIV‑2 virological suppression (but
good HIV‑1 control) in a patient treated with
two NRTIs and either indinavir or an NNRTI
over 5 years, with a good final response to teno‑
fovir (TDF)–3TC and LPV/r  [128] . Genotypic
mutation ana­lysis of the HIV‑2 polymerase gene
showed both reverse transcriptase (Q151M and
M184V) and protease (V71I and L90M) muta‑
tions, further highlighting the fragility of the
initial regimes used. Interestingly, other studies
have suggested that the multi-NRTI resistance
mutation Q151M is selected for more frequently
in HIV‑2 than in HIV‑1 infection [129] . The dan‑
ger of treatment simplification to an NNRTI-
based regime (TDF–didanosine [DDI]–efavi‑
renz) following initial HIV‑1 and HIV‑2 VL
suppression to undetectable levels by stavudine
(D4T)–3TC–LPV/r was shown in another
case study [130] , although it now seems apparent
that this particular combination (TDF/DDI/
efavirenz) is prone to virological failure even
in treating HIV‑1 monoinfection [131] . Despite
the HIV‑1 VL remaining fully suppressed after
the switch, HIV‑2 VL increased, CD4 + T‑cell
count dropped and the acquisition of HIV‑2
K65R and I118V mutations was demonstrated
only 3  months later. A retrospective observa‑
tional study from France, describing ART in 11
HIV-D-infected individuals treated with mul‑
tiple regimes, reported undetectable HIV‑1 and
HIV‑2 VLs in 10 out of 11 patients with their
final ART regimes (LPV/r-based in nine)  [132] .
Of note, baseline HIV‑2 VL was detectable in
only two patients; HIV‑2 VL control was finally
achieved in one with TDF–DRV/r and the inte‑
grase inhibitor raltegravir following multiple
www.futuremedicine.com 11
Review | de Silva, van Tienen, Rowland-Jones & Cotten
other PI-based therapies (and acquisition of
reverse transcriptase [Q151M and M184V] and
protease [I54M and I82F] mutations in the pro‑
cess), whereas the HIV‑2 VL remained detectable
in the other patient despite boosted atazanavir
and boosted LPV-based ART with a V47A muta‑
tion in the HIV‑2 protease gene acquired during
therapy. These reports illustrate the potential dif‑
ficulties in treating HIV-D-infected individuals
and suggest that, especially in patients with a
detectable HIV‑2 VL at baseline, NNRTI and
suboptimal PI-based ART regimes may result in
poor outcomes. If available, inclusion of an inte‑
grase inhibitor when treating HIV‑2 or HIV-D
infection looks promising [133–135] , although
of
the possibility of acquired drug resistance still
exists [136,137] and preliminary analyses suggest
that the genetic resistance profile observed with
raltegravir failure is similar to that seen in HIV‑1
ro
(despite 39% amino acid difference between
HIV‑1 and HIV‑2 integrase genes) [138] .
The two largest studies to date, including
the outcome of ART in HIV-D-infected indi‑
viduals, reach contrasting conclusions (Table 3)
rP
[139,140] . A study in Burkina Faso found poorer
CD4 + T‑cell reconstitution in the first 6 months
of ART in HIV-D- (and HIV‑2)-infected
patients than those with HIV‑1 monoinfection
[139] . No virological monitoring was undertaken.
ho
Heterogeneity in ART regime (including 27.3%
of HIV-D patients treated with an NNRTI-based
regime) and potential errors in HIV-D diag‑
nosis due to the use of rapid tests alone make
interpretation of these findings difficult. The
problem in inadvertent NNRTI use in African
ut
ART programs (due to lack of HIV type-specific
diagnostic capabilities) is also exemplified by a
study from Ghana, where all HIV‑2 and HIV-D
patients were treated with the same regime as
A
HIV‑1 patients [140] . The authors claim that HIV-
D-infected individuals fair better with NNRTI-
based therapy after 6 and 12 months of ART than
those with HIV‑2 monoinfection, with greater
CD4 + T‑cell increases seen in HIV-D patients
at both time points (190 vs 108 cells/mm3 and
219 vs 78 cells/mm3, respectively). There are sev‑
eral possible explanations for this finding. First,
the use of one serological test alone in assigning
HIV-D status could easily have resulted in a
number of false-positive HIV-D cases; as cross-
reacting antibodies between HIV‑1 and HIV‑2
are not uncommon [11] , a proportion may have
actually been infected with HIV‑1 alone. Another
potential confounder is that HIV-D patients in
this study may have commenced ART at a less
12 HIV Ther. (2010) 4(3)
advanced WHO stage than HIV‑2  patients.
Finally, if the finding is valid, it may reflect the
fact that in HIV-D-infected individuals with
advanced immunosuppression, HIV‑1 usually
drives disease progression and HIV‑2 VL is often
undetectable [19,20] ; thus, a reasonable response (at
least with short-term follow-up) to NNRTI‑based
therapy is not unexpected.
Caution is advised in interpreting these find‑
ings as evidence for widespread use of NNRTI-
based therapy in HIV-D-infected patients.
Outcomes may be markedly different in HIV-D-
infected individuals with and without detectable
baseline HIV‑2 VL (the current study lacked suf‑
ficient baseline VLs to explore this); and even in
those with undetectable baseline HIV‑2 VLs, the
theoretical risk exists that as HIV‑1 is controlled
on ART, the potential for HIV‑2 recrudescence
may increase over time. Longer follow-up with
good virological monitoring is required to explore
this. In treating HIV-D-infected individuals,
current advice must be to choose a boosted-PI
regime with adequate HIV‑1 and HIV‑2 activity
[124] , if these drugs are available. It must be appre‑
ciated that the recommendation of different first-
line ART regimes for HIV‑1 and HIV‑2/HIV-
D-infected individuals undoubtedly places more
strain on already stretched logistics in resource-
poor settings. Larger, well-designed studies are
required (which may only be possible through
multicenter networks [141]) where only optimal
regimes such as LPV/r-based ART are used, to
properly assess the virological and immunologi‑
cal response in HIV-D-infected individuals. A
report of eight HIV-D patients commencing
AZT–3TC–LPV/r (six patients with detectable
baseline HIV‑2 VLs) showed fully suppressed
HIV‑2 VL in all individuals by 18–36 months
of follow-up [142] .
Conclusion & future perspective
The superimposition of the HIV‑1 pandemic
on the background of endemic (and declining)
HIV‑2 infection in West Africa represents an
important setting to study the interaction in vivo
between two related retroviruses, both capable
of causing progression to AIDS, but with clearly
different probabilities of doing so in HIV‑1- or
HIV‑2-monoinfected individuals. Currently
available data on the natural history of HIV-D
infection suggest that HIV‑1 outcompetes HIV‑2
in the majority of cases and is the primary cause
of advanced immunodeficiency requiring ART.
This mirrors findings from in  vitro competi‑
tion assays in tissue culture between HIV‑1
future science group
 Dual infection with HIV‑1 & HIV‑2: double trouble or destructive interference? | Review

Table 3. Summary of case series and cohort studies describing response of HIV‑1/2 dual-infected patients on
ART in the HAART era.
HIV-D infected Country ART regime(s) Viral load Follow-up on ART ART response of HIV-D Ref.
patients (n) ana­lysis infected patients
121 Burkina Faso 27% NNRTI regime No Median duration Lower mean CD4 + T‑cell increase [138]
0.8% triple NRTI 17 months (IQR: 5–35) in the first 6 months compared
11.6% IDV regime with HIV‑1 patients
23.1% LPV/r regime Higher proportion of HIV-D
37.2% nelfinavir regime (13.2%) and HIV‑2 (15.4%) deaths
on ART compared with HIV-1
(10.9%), but not significant after
adjusting for age, CD4 + T‑cell
count and WHO stage
57 Ghana All received Baseline VL 6- and 12-month CD4 + T‑cell increase at 6 and [139]
(inadvertent) NNRTI in 14% FU reported 12 months greater in HIV-D than
regime VL on ART HIV‑2 patients (and equivalent to

of
in 56% HIV‑1 group)
Of those with VL measurements
on ART, 75% HIV‑1 undetectable
and 69% HIV‑2 undetectable after
median of 14 months on ART
11

8
France 1–7 different regimes
Final regime LPV/r-based
in 9 out of 11 persons
The Gambia AZT–3TC–LPV/r
Yes

Yes ro
Median FU 2.6 years
(range 0.3–7.6)

18–36 months
HIV‑1 and HIV‑2 VL undetectable
in 10/11 with final regime choice

7/8 patients with undetectable

[132]

[142]
rP
HIV‑1 and 8/8 HIV‑2 VLs at end of
reported FU
5 Côte d’Ivoire 4/5 given NNRTI regime Yes 7–12 months HIV‑1 VL undetectable in 4/5 [161]
1/5 AZT–3TC–nelfinavir treated with NNRTI regime, but
HIV‑2 VL never suppressed
Poor CD4 + T‑cell increase in 3/4
ho

Both HIV‑1 and HIV‑2 VL

suppressed in 1/5 treated with
nelfinavir regime
Individual case reports excluded, but discussed in main text.
3TC: Lamuvidine; AZT: Zidovudine; FU: Follow-up; HIV-D: HIV‑1/2 dual; IDV: Indinavir; IQR: Interquartile range; LPV/r: Lopinavir/ritonavir; NNRTI: Non-nucleoside
reverse transcriptase inhibitor; NRTI: Nucleos(t)ide reverse transcriptase inhibitor; VL: Viral load.
ut

group M and HIV‑2 strains  [143] , although the
exact mechanisms underlying the relative success
of HIV‑1 over HIV‑2 are far from clear. There
is no evidence to suggest that coinfection with
A
HIV‑1 infection, which are yet to be identified
despite 25 years of research. Apart from the epi‑
demiological challenges in reliably identifying
such individuals (and appropriate controls), the

both HIV‑1 and HIV‑2 results in a significant
synergistic relationship and therefore in a worse
outcome for HIV-D-infected individuals, when
compared with those with HIV‑1 monoinfec‑
tion. Arguably the most valuable area of study
would be that of cross-reactive immune responses
in HIV‑2-infected individuals that may prevent
superinfection with HIV‑1, but it seems clear
that at a population level, there is no partial
protection as initially proposed. If it were pos‑
sible to identify HIV‑2-infected individuals that
remain monoinfected despite repeated potential
exposure to HIV‑1, it may be possible to identify
innate and adaptive immune responses desirable
in a prophylactic HIV‑1 vaccine. This would rep‑
resent true correlates of protective immunity in
potential for doing so is also rapidly diminishing
as HIV‑2 prevalence falls in West Africa.
Acknowledgements
The authors would like to thank Maarten Schim van der
Loeff for helpful comments on the manuscript.
Financial & competing interests disclosure
TI de Silva is supported by a Medical Research Council
(UK) Clinical Research Training Fellowship. The authors
have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in
or financial conflict with the subject matter or materials
discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of
this manuscript.

future science group www.futuremedicine.com 13

Review | de Silva, van Tienen, Rowland-Jones & Cotten

Executive summary
„„ The diagnosis of true HIV‑1/2 dual infection poses challenges due to cross-reactive antibodies between HIV‑1 and HIV‑2.
– The gold standard of dual infection diagnosis is PCR, but false negatives may occur as HIV‑2 provirus load can be very low in
advanced HIV‑1/2 dual infection.
– Robust algorithms including several serological methods, combined with molecular diagnostics, are ideal, but may not be feasible in
resource-poor settings where the majority of HIV‑1/2 dual infections are found.
„„ In countries where HIV‑1 and HIV‑2 are endemic, the prevalence of HIV‑1/2 dual infection is on the whole lower than that of
either monoinfection.
– The prevalence of HIV‑1/2 dual infection varies greatly across West Africa and different population groups.
– Due to the timing of the HIV‑2 and HIV‑1 epidemics in West Africa, it is likely that HIV‑2 infection precedes HIV‑1 infection in the
majority of dually infected cases, although there is a paucity of published data to support this.
„„ There is no current evidence for HIV‑1 and HIV‑2 having recombined in natural infection and strong viral barriers may exist against
this occurring.
– Incompatibility between HIV‑1 and HIV‑2 in a sequence element called the dimer initiation site (DIS) required for RNA genome dimer
formation makes an HIV‑1–HIV‑2 recombination event unlikely in vivo.
Although several cross-reactive responses and inhibitory mechanisms have been demonstrated whereby HIV‑2 may prevent HIV‑1

of
„„

superinfection, the weight of epidemiological evidence does not support such a protective effect.
– Despite one early study from Dakar showing a 68% protective effect of HIV‑2 on risk of HIV‑1 superinfection, several subsequent
studies from West Africa have failed to replicate this finding.
– Cytotoxic T-lymphocytes from HIV‑2-infected individuals with certain HLA alleles, but not others, show cross-reactivity against HIV‑1

ro
proteins. HIV‑1 cross-neutralizing antibody responses are also found in some HIV‑2-infected individuals, but are low titer.
– T‑cell responses against HIV‑2 Gag correlate inversely with HIV‑1 viral loads in HIV‑1/2 dual-infected individuals and higher
frequencies of IFN-g secreting HIV‑1-specific CD4 + T cells are seen in HIV-D patients when compared with those with
HIV‑1 monoinfection.
rP
„„ HIV‑2 infection does not appear to attenuate the course of HIV‑1 infection and disease progression is similar in HIV‑1/2 dual-infected and
HIV‑1 monoinfected individuals.
– Mortality and HIV‑1 viral load are similar in HIV‑1/2 dual-infected and HIV‑1 monoinfected individuals matched for disease stage.
– HIV‑1 appears to outcompete HIV‑2 with progressive disease in HIV‑1/2 dual infection, as evidenced by low or undetectable HIV‑2
plasma viral and proviral loads (when compared with high viral loads seen in HIV‑2 monoinfected individuals with
advanced disease).
ho

„„ Antiretroviral therapy in HIV‑1/2 dual-infected individuals should include an appropriate boosted-protease inhibitor-based regime with
activity against both HIV‑1 and HIV‑2.
– HIV‑1/2 dual-infected individuals with undetectable HIV‑2 viral loads may show a good initial response to non-nucleoside reverse
transcriptase inhibitor-based regimes, even though HIV‑2 is naturally resistant to non-nucleoside reverse transcriptase inhibitors; but
the risk of HIV‑2 recrudescence exists as HIV‑1 is controlled. There is no evidence currently to guide regime choice based on HIV‑2
viral load.
ut

– Some protease inhibitors used in HIV‑1 therapy are more active against HIV‑2 than others (e.g., lopinavir, saquinavir and darunavir)
and current recommendations should be to use a protease inhibitor-based regime with one of these drugs, where possible, when
treating HIV‑1/2 dual infection.
A

Bibliography
Papers of special note have been highlighted as:
n of interest
1 de Silva TI, Cotten M,
Rowland-Jones SL: HIV‑2: the forgotten
AIDS virus. Trends Microbiol. 16(12),
588–595 (2008).
2 Jaffar S, Grant AD, Whitworth J,
Smith PG, Whittle H: The natural
history of HIV‑1 and HIV‑2 infections in
adults in Africa: a literature review. Bull.
World Health Organ. 82(6), 462–469
(2004).
3 Hahn BH, Shaw GM, De Cock KM,
Sharp PM: AIDS as a zoonosis: scientific and
public health implications. Science 287(5453),
607–614 (2000).
4 Martinez-Steele E, Awasana AA, Corrah T
et al.: Is HIV‑2-induced AIDS different
from HIV‑1-associated AIDS? Data from a
West African clinic. AIDS 21(3), 317–324
(2007).
5 Cot MC, Poulain M, Delagneau JF,
Peeters M, Brun-Vezinet F: Dual HIV‑1 and
HIV‑2 infection in West Africa supported by
synthetic peptide ana­lysis. AIDS Res. Hum.
Retroviruses 4(4), 239–241 (1988).
6 Evans LA, Moreau J, Odehouri K et al.:
Simultaneous isolation of HIV‑1 and HIV‑2
from an AIDS patient. Lancet 2(8625),
1389–1391 (1988).
7 Rayfield M, De Cock K, Heyward W et al.:
Mixed human immunodeficiency virus (HIV)
infection in an individual: demonstration of
both HIV type 1 and type 2 proviral
sequences by using polymerase chain reaction.
J. Infect. Dis. 158(6), 1170–1176 (1988).
8 Nkengasong JN, Maurice C, Koblavi S
et al.: Field evaluation of a combination of
monospecific enzyme-linked
immunosorbent assays for type-specific
diagnosis of human immunodeficiency virus
type 1 (HIV‑1) and HIV‑2 infections in
HIV-seropositive persons in Abidjan, Ivory
Coast. J. Clin. Microbiol. 36(1), 123–127
(1998).
9 Tedder RS, O’Connor T, Hughes A,
N’Jie H, Corrah T, Whittle H: Envelope
cross-reactivity in western blot for HIV‑1
and HIV‑2 may not indicate dual infection.
Lancet 2(8617), 927–930 (1988).

14 HIV Ther. (2010) 4(3) future science group

 Dual infection with HIV‑1 & HIV‑2: double trouble or destructive interference?
10 De Cock KM, Porter A, Kouadio J et al.:
Rapid and specific diagnosis of HIV‑1 and
HIV‑2 infections: an evaluation of testing
strategies. AIDS 4(9), 875–878 (1990).
11 De Cock KM, Porter A, Kouadio J et al.:
Cross-reactivity on western blots in HIV‑1
and HIV‑2 infections. AIDS 5(7), 859–863
(1991).
12 Andersson S, da Silva Z, Norrgren H, Dias F,
Biberfeld G: Field evaluation of alternative
testing strategies for diagnosis and
differentiation of HIV‑1 and HIV‑2 infections
in an HIV‑1 and HIV‑2-prevalent area. AIDS
11(15), 1815–1822 (1997).
13 Peeters M, Gershy-Damet GM, Fransen K
et al.: Virological and polymerase chain
reaction studies of HIV‑1/HIV‑2 dual
infection in Côte d’Ivoire. Lancet 340(8815),
339–340 (1992).
14 Berry N, Ariyoshi K, Jobe O et al.: HIV
type 2 proviral load measured by quantitative
polymerase chain reaction correlates with
CD4 + lymphopenia in HIV type 2-infected
individuals. AIDS Res. Hum. Retroviruses
10(8), 1031–1037 (1994).
15 Ariyoshi K, Berry N, Wilkins A et al.:
A community-based study of human
immunodeficiency virus type 2 provirus load
in rural village in West Africa. J. Infect. Dis.
173(1), 245–248 (1996).
16 Ishikawa K, Fransen K, Ariyoshi K et al.:
Improved detection of HIV‑2 proviral DNA
ho
in dually seroreactive individuals by PCR.
AIDS 12(12), 1419–1425 (1998).
17 Walther-Jallow L, Andersson S, da Silva Z,
Biberfeld G: High concordance between
polymerase chain reaction and antibody
testing of specimens from individuals dually
ut
infected with HIV types 1 and 2 in
Guinea-Bissau, West Africa. AIDS Res. Hum.
Retroviruses 15(11), 957–962 (1999).
18 Rouet F, Ekouevi DK, Inwoley A et al.: Field
A
evaluation of a rapid human
immunodeficiency virus (HIV) serial
serologic testing algorithm for diagnosis and
differentiation of HIV type 1 (HIV‑1),
HIV‑2, and dual HIV‑1-HIV‑2 infections in
West African pregnant women. J. Clin.
Microbiol. 42(9), 4147–4153 (2004).
19 Alabi AS, Jaffar S, Ariyoshi K et al.: Plasma
viral load, CD4 cell percentage, HLA and
survival of HIV‑1, HIV‑2, and dually infected
Gambian patients. AIDS 17(10), 1513–1520
(2003).
n A good comparison of the risk of mortality,
as well as HIV‑1 and HIV‑2 plasma viral
load, in HIV‑1/2 dual infection when
compared with HIV‑1 and HIV‑2
monoinfection, stratified by disease stage.
future science group
20 Koblavi-Deme S, Kestens L, Hanson D et al.:
Differences in HIV‑2 plasma viral load and
immune activation in HIV‑1 and HIV‑2
dually infected persons and those infected
with HIV‑2 only in Abidjan, Côte d’Ivoire.
AIDS 18(3), 413–419 (2004).
21 Sarr AD, Hamel DJ, Thior I et al.: HIV‑1 and
HIV‑2 dual infection: lack of HIV‑2 provirus
correlates with low CD4 + lymphocyte counts.
AIDS 12(2), 131–137 (1998).
22 Sarr AD, Popper S, Thior I et al.: Relation
between HIV‑2 proviral load and CD4 +
lymphocyte count differs in monotypic and
dual HIV infections. J. Hum. Virol. 2(1),
45–51 (1999).
23 Schim van der Loeff MF, Aaby P: Towards a
better understanding of the epidemiology of
of
HIV‑2. AIDS 13(Suppl. A) S69–S84 (1999).
24 Clavel F, Guetard D, Brun-Vezinet F et al.:
Isolation of a new human retrovirus from
West African patients with AIDS. Science
ro
233(4761), 343–346 (1986).
25 Clavel F, Mansinho K, Chamaret S et al.:
Human immunodeficiency virus type 2
infection associated with AIDS in West Africa.
N. Engl. J. Med. 316(19), 1180–1185 (1987).
rP
26 Brun-Vezinet F, Rey MA, Katlama C et al.:
Lymphadenopathy-associated virus type 2 in
AIDS and AIDS-related complex. Clinical
and virological features in four patients.
Lancet 1(8525), 128–132 (1987).
27 Lemey P, Pybus OG, Wang B, Saksena NK,
Salemi M, Vandamme AM: Tracing the
origin and history of the HIV‑2 epidemic.
Proc. Natl Acad. Sci. USA 100(11),
6588–6592 (2003).
28 Poulsen AG, Kvinesdal B, Aaby P et al.:
Prevalence of and mortality from human
immunodeficiency virus type 2 in Bissau,
West Africa. Lancet 1(8642), 827–831 (1989).
29 Wilkins A, Ricard D, Todd J, Whittle H,
Dias F, Paulo Da Silva A: The epidemiology
of HIV infection in a rural area of Guinea-
Bissau. AIDS 7(8), 1119–1122 (1993).
30 Poulsen AG, Aaby P, Jensen H, Dias F: Risk
factors for HIV‑2 seropositivity among older
people in Guinea-Bissau. A search for the
early history of HIV‑2 infection. Scand.
J. Infect. Dis. 32(2), 169–175 (2000).
31 Pepin J, Plamondon M, Alves AC, Beaudet M,
Labbe AC: Parenteral transmission during
excision and treatment of tuberculosis and
trypanosomiasis may be responsible for the
HIV‑2 epidemic in Guinea-Bissau. AIDS
20(9), 1303–1311 (2006).
32 Jensen ML, Dave S, Schimvan der Loeff M
et al.: Vaccinia scars associated with improved
survival among adults in rural Guinea-Bissau.
PLoS ONE 1, e101 (2006).
www.futuremedicine.com
| Review
33 Smallman-Raynor M, Cliff A: The spread of
human immunodeficiency virus type 2 into
Europe: a geographical ana­lysis.
Int. J. Epidemiol. 20(2), 480–489 (1991).
34 Matheron S, Mendoza-Sassi G, Simon F,
Olivares R, Coulaud JP, Brun-Vezinet F:
HIV‑1 and HIV‑2 AIDS in African patients
living in Paris. AIDS 11(7), 934–936 (1997).
35 Soriano V, Gomes P, Heneine W et al.:
Human immunodeficiency virus type 2
(HIV‑2) in Portugal: clinical spectrum,
circulating subtypes, virus isolation, and
plasma viral load. J. Med. Virol. 61(1),
111–116 (2000).
36 Dougan S, Patel B, Tosswill JH, Sinka K:
Diagnoses of HIV‑1 and HIV‑2 in England,
Wales, and Northern Ireland associated with
west Africa. Sex. Transm. Infect. 81(4),
338–341 (2005).
37 Barin F, Cazein F, Lot F et al.: Prevalence of
HIV‑2 and HIV‑1 group O infections among
new HIV diagnoses in France: 2003–2006.
AIDS 21(17), 2351–2353 (2007).
38 Buve A, Bishikwabo-Nsarhaza K,
Mutangadura G: The spread and effect of
HIV‑1 infection in sub-Saharan Africa.
Lancet 359(9322), 2011–2017 (2002).
39 Mansson F, Alves A, Silva ZJ et al.: Trends of
HIV‑1 and HIV‑2 prevalence among pregnant
women in Guinea-Bissau, West Africa:
possible effect of the civil war 1998–1999.
Sex. Transm. Infect. 83(6), 463–467 (2007).
40 Norrgren H, Andersson S, Biague AJ et al.:
Trends and interaction of HIV‑1 and HIV‑2
in Guinea-Bissau, west Africa: no protection
of HIV‑2 against HIV‑1 infection. AIDS
13(6), 701–707 (1999).
41 van Tienen C, Schim van der Loeff MF,
Zaman SM et al.: Two distinct epidemics: the
rise of HIV‑1 and decline of HIV‑2 infection
between 1990 and 2007 in rural Guinea-
Bissau. J. Acquir. Immune Defic. Syndr. (2009)
(Epub ahead of print).
42 Poulsen AG, Aaby P, Gottschau A et al.:
HIV‑2 infection in Bissau, West Africa,
1987–1989: incidence, prevalences, and routes
of transmission. J. Acquir. Immune Defic.
Syndr. 6(8), 941–948 (1993).
43 Larsen O, da Silva Z, Sandstrom A et al.:
Declining HIV‑2 prevalence and incidence
among men in a community study from
Guinea-Bissau. AIDS 12(13), 1707–1714
(1998).
44 da Silva ZJ, Oliveira I, Andersen A et al.:
Changes in prevalence and incidence of
HIV‑1, HIV‑2 and dual infections in urban
areas of Bissau, Guinea-Bissau: is HIV‑2
disappearing? AIDS 22(10), 1195–1202
(2008).
15
Review | de Silva, van Tienen, Rowland-Jones & Cotten
45 Mbizvo MT, Mashu A, Chipato T, Makura E,
Bopoto R, Fottrell PF: Trends in HIV‑1 and
HIV‑2 prevalence and risk factors in pregnant
women in Harare, Zimbabwe. Cent. Afr.
J. Med. 42(1), 14–21 (1996).
46 Humphrey JH, Nathoo KJ, Hargrove JW
et al.: HIV‑1 and HIV‑2 prevalence and
associated risk factors among postnatal
women in Harare, Zimbabwe. Epidemiol.
Infect. 135(6), 933–942 (2007).
47 Schoch OD, Rieder HL: Characteristics of
sputum smear-positive tuberculosis patients
with and without HIV infection in a hospital
in Zimbabwe. Eur. Respir. J. 9(2), 284–287
(1996).
48 Gregson S, Mason PR, Garnett GP et al.: A
rural HIV epidemic in Zimbabwe? Findings
57 De Cock KM, Adjorlolo G, Ekpini E et al.:
Epidemiology and transmission of HIV‑2.
Why there is no HIV‑2 pandemic. JAMA
270(17), 2083–2086 (1993).
58 Djomand G, Greenberg AE,
Sassan‑Morokro M et al.: The epidemic of
HIV/AIDS in Abidjan, Côte d’Ivoire: a review
of data collected by Projet RETRO-CI from
1987 to 1993. J. Acquir. Immune Defic. Syndr.
Hum. Retrovirol. 10(3), 358–365 (1995).
59 Ghys PD, Diallo MO, Ettiegne-Traore V
et al.: Increase in condom use and decline in
HIV and sexually transmitted diseases among
female sex workers in Abidjan, Côte d’Ivoire,
1991–1998. AIDS 16(2), 251–258 (2002).
60 Nkengasong JN, Kestens L, Ghys PD et al.:
Dual infection with human immunodeficiency
68 Wildum S, Schindler M, Munch J,
Kirchhoff F: Contribution of Vpu, Env, and
Nef to CD4 down-modulation and resistance
of human immunodeficiency virus
type 1-infected T cells to superinfection.
J. Virol. 80(16), 8047–8059 (2006).
69 Dirac AM, Huthoff H, Kjems J, Berkhout B:
Requirements for RNA heterodimerization of
the human immunodeficiency virus type 1
(HIV‑1) and HIV‑2 genomes. J. Gen. Virol.
83(Pt 10), 2533–2542 (2002).
n Suggests that HIV‑1–HIV‑2 recombination
may be severely restricted at the level of
RNA dimerization.
70 Chin MP, Chen J, Nikolaitchik OA, Hu WS:
Molecular determinants of HIV‑1
intersubtype recombination potential.

from a population-based survey. Int. J. STD
AIDS 12(3), 189–196 (2001).
49 Gregson S, Garnett GP, Nyamukapa CA
et al.: HIV decline associated with behavior
of
virus type 1 and type 2: impact on HIV type 1 Virology 363(2), 437–446 (2007).
viral load and immune activation markers in
71 Chin MP, Lee SK, Chen J et al.: Long-range
HIV-seropositive female sex workers in
recombination gradient between HIV‑1
Abidjan, Ivory Coast. AIDS Res. Hum.
subtypes B and C variants caused by sequence
Retroviruses 16(14), 1371–1378 (2000).

change in eastern Zimbabwe. Science
311(5761), 664–666 (2006).
50 Rubsamen-Waigmann H, Maniar J, Gerte S
et al.: High proportion of HIV‑2 and
HIV‑1/2 double-reactive sera in two Indian
states, Maharashtra and Goa: first appearance
of an HIV‑2 epidemic along with an HIV‑1
epidemic outside of Africa. Zentralbl.
Bakteriol. 280(3), 398–402 (1994).
51 Pfutzner A, Dietrich U, von Eichel U et al.:
HIV‑1 and HIV‑2 infections in a high-risk
ho
ro
differences in the dimerization initiation
61 Sarr AD, Sankale JL, Hamel DJ et al.: signal region. J. Mol. Biol. 377(5), 1324–1333
Interaction with human immunodeficiency (2008).
virus (HIV) type 2 predicts HIV type 1
72 Chin MP, Rhodes TD, Chen J, Fu W,
genotype. Virology 268(2), 402–410 (2000).
Hu WS: Identification of a major restriction
rP
62 Andersson S, Norrgren H, Dias F, in HIV‑1 intersubtype recombination. Proc.
Biberfeld G, Albert J: Molecular Natl Acad. Sci. USA 102(25), 9002–9007
characterization of human immunodeficiency (2005).
virus (HIV)-1 and -2 in individuals from
73 Yamaguchi J, Vallari A, Ndembi N et al.:
Guinea-Bissau with single or dual infections:
HIV type 2 intergroup recombinant identified
predominance of a distinct HIV‑1 subtype
in Cameroon. AIDS Res. Hum. Retroviruses

population in Bombay, India: evidence for the
spread of HIV‑2 and presence of a divergent
HIV‑1 subtype. J. Acquir. Immune Defic.
Syndr. 5(10), 972–977 (1992).
52 Rodrigues JJ, Mehendale SM, Shepherd ME
et al.: Risk factors for HIV infection in people
ut
A/G recombinant in West Africa. Virology
24(1), 86–91 (2008).
262(2), 312–320 (1999).
74 Ibe S, Yokomaku, Y, Shiino T et al.: HIV‑2
63 Sagoe KW, Britton S, Mingle JA, Affram K,
CRF01_AB: first circulating recombinant
Djokoto A, Sonnerborg A: Similar HIV‑1
form of HIV‑2. Presented at: 17th Conference
subtype A V3 loop sequences are found in
on Retroviruses and Opportunistic Infections.
dual HIV‑1/HIV‑2 and HIV‑1-only
San Francisco, USA, 16–19 February 2010

attending clinics for sexually transmitted
diseases in India. BMJ 311(7000), 283–286
(1995).
53 Ramalingam S, Kannangai R, Prakash KJ,
A
seropositives in Ghana. AIDS Res. Hum.
(Abstract 443).
Retroviruses 15(8), 775–779 (1999).
75 Mukherjee S, Lee HL, Ron Y, Dougherty JP:
64 Sarr AD, Sankale JL, Gueye-Ndiaye A,
Proviral progeny of heterodimeric virions
Essex M, Mboup S, Kanki PJ: Genetic
reveal a high crossover rate for human

Jesudason MV, Sridharan G: Per-exposure
rate of transmission of HIV‑1, HIV‑1/2, and
HIV‑2 from women to men may be higher in
India. J. Acquir. Immune Defic. Syndr. 25(1),
97–98 (2000).
54 Dietrich U, Maniar JK,
Rubsamen‑Waigmann H: The epidemiology
of HIV in India. Trends Microbiol. 3(1),
17–21 (1995).
55 Kannangai R, Ramalingam S, Castillo RC
et al.: HIV‑2 status in southern India. Trans.
R. Soc. Trop. Med. Hyg. 93(1), 30–31 (1999).
56 Kannangai R, Ramalingam S,
Vijayakumar TS, Prabu K, Jesudason MV,
Sridharan G: HIV‑2 sub-epidemic not
gathering speed: experience from a tertiary
care center in south India. J. Acquir. Immune
Defic. Syndr. 32(5), 573–575 (2003).
ana­lysis of HIV type 2 in monotypic and dual
immunodeficiency virus type 2. J. Virol.
HIV infections. AIDS Res. Hum. Retroviruses
80(24), 12402–12407 (2006).
16(3), 295–298 (2000).
76 Motomura K, Chen J, Hu WS: Genetic
65 Meloni ST, Kim B, Sankale JL et al.: Distinct
recombination between human
human immunodeficiency virus type 1
immunodeficiency virus type 1 (HIV‑1) and
subtype A virus circulating in West Africa:
HIV‑2, two distinct human lentiviruses.
sub-subtype A3. J. Virol. 78(22),
J. Virol. 82(4), 1923–1933 (2008).
12438–12445 (2004).
77 Boyko V, Leavitt M, Gorelick R et al.:
66 Meloni ST, Sankale JL, Hamel DJ et al.:
Coassembly and complementation of Gag
Molecular epidemiology of human
proteins from HIV‑1 and HIV‑2, two distinct
immunodeficiency virus type 1 sub-subtype
human pathogens. Mol. Cell 23(2), 281–287
A3 in Senegal from 1988 to 2001. J. Virol.
(2006).
78(22), 12455–12461 (2004).
78 Kaye JF, Lever AM: Nonreciprocal packaging
67 Gottlieb GS, Sow PS, Hawes SE et al.:
of human immunodeficiency virus type 1 and
Molecular epidemiology of dual HIV‑1/
type 2 RNA: a possible role for the p2 domain
HIV‑2 seropositive adults from Senegal, West
of Gag in RNA encapsidation. J. Virol. 72(7),
Africa. AIDS Res. Hum. Retroviruses 19(7),
5877–5885 (1998).
575–584 (2003).

16 HIV Ther. (2010) 4(3) future science group

 Dual infection with HIV‑1 & HIV‑2: double trouble or destructive interference?
79 Curlin ME, Gottlieb GS, Hawes SE et al.:
No evidence for recombination between HIV
type 1 and HIV type 2 within the envelope
region in dually seropositive individuals from
Senegal. AIDS Res. Hum. Retroviruses 20(9),
958–963 (2004).
80 Travers K, Mboup S, Marlink R et al.:
Natural protection against HIV‑1 infection
provided by HIV‑2. Science 268(5217),
1612–1615 (1995).
81 Greenberg AE, Wiktor SZ, DeCock KM,
Smith P, Jaffe HW, Dondero TJ Jr: HIV‑2
and natural protection against HIV‑1
infection. Science 272(5270), 1959–1960
(1996).
82 Kanki PJ, Eisen G, Travers KU et al.:
Response: HIV‑2 and natural protection
against HIV‑1 infection. Science 272(5270),
1959b-1960b (1996).
83 Ariyoshi K, Schim van der Loeff M,
Sabally S, Cham F, Corrah T, Whittle H:
Does HIV‑2 infection provide cross-
protection against HIV‑1 infection? AIDS
11(8), 1053–1054 (1997).
84 Wiktor SZ, Nkengasong JN, Ekpini ER et al.:
Lack of protection against HIV‑1 infection
among women with HIV‑2 infection. AIDS
13(6), 695–699 (1999).
85 Aaby P, Poulsen AG, Larsen O et al.: Does
HIV‑2 protect against HIV‑1 infection? AIDS
11(7), 939–940 (1997).
86 Schim van der Loeff MF, Aaby P, Aryioshi K
ho
et al.: HIV‑2 does not protect against HIV‑1
infection in a rural community in Guinea-
Bissau. AIDS 15(17), 2303–2310 (2001).
87 Greenberg AE: Possible protective effect of
HIV‑2 against incident HIV‑1 infection:
ut
review of available epidemiological and
in vitro data. AIDS 15(17), 2319–2321 (2001).
n Clear and concise overview of the
epidemiology on protection against HIV‑1
by HIV‑2.
A
88 Travers KU, Eisen GE, Marlink RG et al.:
Protection from HIV‑1 infection by HIV‑2.
AIDS 12(2), 224–225 (1998).
89 Pinto LA, Covas MJ, Victorino RM: T-helper
cross reactivity to viral recombinant proteins
in HIV‑2-infected patients. AIDS 7(10),
1389–1391 (1993).
90 Bertoletti A, Cham F, McAdam S et al.:
Cytotoxic T cells from human
immunodeficiency virus type 2-infected
patients frequently cross-react with different
human immunodeficiency virus type 1 clades.
J. Virol. 72(3), 2439–2448 (1998).
91 Rowland-Jones S, Sutton J, Ariyoshi K et al.:
HIV-specific cytotoxic T cells in HIV-
exposed but uninfected Gambian women.
Nat. Med. 1(1), 59–64 (1995).
future science group
92 Lopes AR, Jaye A, Dorrell L et al.: Greater
CD8 + TCR heterogeneity and functional
flexibility in HIV‑2 compared with HIV‑1
infection. J. Immunol. 171(1), 307–316
(2003).
93 Gotch F, McAdam SN, Allsopp CE et al.:
Cytotoxic T cells in HIV2 seropositive
Gambians. Identification of a virus-specific
MHC-restricted peptide epitope. J. Immunol.
151(6), 3361–3369 (1993).
94 Rowland-Jones S, Colbert RA, Dong T et al.:
Distinct recognition of closely-related HIV‑1
and HIV‑2 cytotoxic T‑cell epitopes presented
by HLA-B*2703 and B*2705. AIDS 12(11),
1391–1393 (1998).
95 Duvall MG, Jaye A, Dong T et al.:
Maintenance of HIV-specific CD4 T cell help
+ 2(2), 95–100 (1988).
of
distinguishes HIV‑2 from HIV‑1 infection.
J. Immunol. 176(11), 6973–6981 (2006).
96 Rosenberg ES, Billingsley JM, Caliendo AM
et al.: Vigorous HIV‑1-specific CD4 + T cell
ro
responses associated with control of viremia.
Science 278(5342), 1447–1450 (1997).
97 Kiepiela P, Leslie AJ, Honeyborne I et al.:
Dominant influence of HLA-B in mediating
the potential co-evolution of HIV and HLA.
rP
Nature 432(7018), 769–775 (2004).
98 Leligdowicz A, Yindom LM, Onyango C et al.:
Robust Gag-specific T cell responses
characterize viremia control in HIV‑2 infection.
J. Clin. Invest. 117(10), 3067–3074 (2007).
99 Zheng NN, Kiviat NB, Sow PS et al.:
Comparison of human immunodeficiency
virus (HIV)-specific T‑cell responses in
HIV‑1- and HIV‑2-infected individuals in
Senegal. J. Virol. 78(24), 13934–13942
(2004).
100 Zheng NN, McElrath MJ, Sow PS et al.:
Role of human immunodeficiency virus
(HIV)-specific T‑cell immunity in control of
dual HIV‑1 and HIV‑2 infection. J. Virol.
81(17), 9061–9071 (2007).
n Assessment of T‑cell responses in
immune control of HIV‑1 and HIV‑2 in
dual infection.
101 Clavel F, Brun-Vezinet F, Guetard D et al.:
[LAV type II: a second retrovirus associated
with AIDS in West Africa]. C. R. Acad.
Sci. III 302(13), 485–488 (1986).
102 Clavel F, Guyader M, Guetard D, Salle M,
Montagnier L, Alizon M: Molecular cloning
and polymorphism of the human immune
deficiency virus type 2. Nature 324(6098),
691–695 (1986).
103 Guyader M, Emerman M, Sonigo P, Clavel F,
Montagnier L, Alizon M: Genome
organization and transactivation of the
human immunodeficiency virus type 2.
Nature 326(6114), 662–669 (1987).
www.futuremedicine.com
| Review
104 Bottiger B, Karlsson A, Andreasson PA et al.:
Envelope cross-reactivity between human
immunodeficiency virus types 1 and 2
detected by different serological methods:
correlation between cross-neutralization and
reactivity against the main neutralizing site.
J. Virol. 64(7), 3492–3499 (1990).
105 Rodriguez SK, Sarr AD, Macneil A et al.:
Comparison of heterologous neutralizing
antibody responses between HIV‑1 and
HIV‑2 infected Senegalese patients: distinct
patterns of breadth and magnitude
distinguish HIV‑1 and HIV‑2. J. Virol.
81(10), 5331–5338 (2007).
106 Weiss RA, Clapham PR, Weber JN et al.:
HIV‑2 antisera cross-neutralize HIV‑1. AIDS
107 Otten RA, Ellenberger DL, Adams DR et al.:
Identification of a window period for
susceptibility to dual infection with two
distinct human immunodeficiency virus type
2 isolates in a Macaca nemestrina (pig-tailed
macaque) model. J. Infect. Dis. 180(3),
673–684 (1999).
108 Gunthard HF, Huber M, Kuster H et al.:
HIV‑1 superinfection in an HIV‑2-infected
woman with subsequent control of HIV‑1
plasma viremia. Clin. Infect. Dis. 48(11),
e117–e120 (2009).
109 Patterson LJ, Peng B, Abimiku AG et al.:
Cross-protection in NYVAC-HIV‑1-
immunized/HIV‑2-challenged but not in
NYVAC-HIV‑2-immunized/SHIV-
challenged rhesus macaques. AIDS 14(16),
2445–2455 (2000).
110 Arya SK, Gallo RC: Human immunodeficiency
virus (HIV) type 2-mediated inhibition of HIV
type 1: a new approach to gene therapy of
HIV-infection. Proc. Natl Acad. Sci. USA
93(9), 4486–4491 (1996).
111 Dern K, Rubsamen-Waigmann H, Unger RE:
Inhibition of HIV type 1 replication by
simultaneous infection of peripheral blood
lymphocytes with human immunodeficiency
virus types 1 and 2. AIDS Res. Hum.
Retroviruses 17(4), 295–309 (2001).
112 Kokkotou EG, Sankale JL, Mani I et al.:
In vitro correlates of HIV‑2-mediated HIV‑1
protection. Proc. Natl Acad. Sci. USA 97(12),
6797–6802 (2000).
113 Otten RA, Adams DR, Kim CN et al.:
Chronic HIV‑2 infection protects against
total CD4 + cell depletion and rapid disease
progression induced by SHIV89.6p challenge.
AIDS 18(8), 1127–1135 (2004).
114 Kestens L, Brattegaard K, Adjorlolo G et al.:
Immunological comparison of HIV‑1-,
HIV‑2- and dually-reactive women delivering
in Abidjan, Cote d’Ivoire. AIDS 6(8),
803–807 (1992).
17
Review | de Silva, van Tienen, Rowland-Jones & Cotten
115 Kassim S, Sassan-Morokro M, Ackah A et al.:
Two-year follow-up of persons with HIV‑1-
and HIV‑2-associated pulmonary
tuberculosis treated with short-course
chemotherapy in West Africa. AIDS 9(10),
1185–1191 (1995).
116 Holmgren B, da Silva Z, Vastrup P et al.:
Mortality associated with HIV‑1, HIV‑2, and
HTLV-I single and dual infections in a
middle-aged and older population in
Guinea-Bissau. Retrovirology 4, 85 (2007).
117 Schim van der Loeff MF, Jaffar S, Aveika AA
et al.: Mortality of HIV‑1, HIV‑2 and HIV‑1/
HIV‑2 dually infected patients in a
clinic-based cohort in The Gambia. AIDS
16(13), 1775–1783 (2002).
118 Seng R, Gustafson P, Gomes VF et al.:
Community study of the relative impact of
HIV‑1 and HIV‑2 on intrathoracic
tuberculosis. AIDS 16(7), 1059–1066 (2002).
119 Andersson S, Norrgren H, da Silva Z et al.:
Plasma viral load in HIV‑1 and HIV‑2 singly
and dually infected individuals in Guinea-
Bissau, West Africa: significantly lower
plasma virus set point in HIV‑2 infection
than in HIV‑1 infection. Arch. Intern. Med.
160(21), 3286–3293 (2000).
120 Dorrell L, Willcox BE, Jones EY et al.:
Cytotoxic T lymphocytes recognize
structurally diverse, clade-specific and
cross-reactive peptides in human
immunodeficiency virus type-1 gag through
ho
HLA-B53. Eur. J. Immunol. 31(6), 1747–1756
(2001).
121 Isaka Y, Miki S, Kawauchi S et al.: A single
amino acid change at Leu-188 in the reverse
transcriptase of HIV‑2 and SIV renders them
sensitive to non-nucleoside reverse
ut
transcriptase inhibitors. Arch. Virol. 146(4),
743–755 (2001).
122 Witvrouw M, Pannecouque C, Van
Laethem K, Desmyter J, De Clercq E,
A
Vandamme AM: Activity of non-nucleoside
reverse transcriptase inhibitors against HIV‑2
and SIV. AIDS 13(12), 1477–1483 (1999).
123 Desbois D, Roquebert B, Peytavin G et al.:
In vitro phenotypic susceptibility of human
immunodeficiency virus type 2 clinical
isolates to protease inhibitors. Antimicrob.
Agents Chemother. 52(4), 1545–1548 (2008).
124 Brower ET, Bacha UM, Kawasaki Y, Freire E:
Inhibition of HIV‑2 protease by HIV‑1
protease inhibitors in clinical use. Chem. Biol.
Drug Des. 71(4), 298–305 (2008).
125 Masse S, Lu X, Dekhtyar T et al.: In vitro
selection and characterization of human
immunodeficiency virus type 2 with
decreased susceptibility to lopinavir.
Antimicrob. Agents Chemother. 51(9),
3075–3080 (2007).
18
126 Schutten M, van der Ende ME,
Osterhaus AD: Antiretroviral therapy in
patients with dual infection with human
immunodeficiency virus types 1 and 2. N.
Engl. J. Med. 342(23), 1758–1760 (2000).
127 Smith RA, Ba SN, Hawes SE et al.: Toward
optimal antiretroviral therapy for HIV‑2: can
genotypic and phenotypic drug resistance
testing help guide therapy in HIV‑2?.
Presented at: 17th Conference on Retroviruses
and Opportunistic Infections. San Francisco,
USA, 16–19 February 2010 (Abstract 597).
128 Maniar JK, Damond F, Kamath RR,
Mandalia S, Surjushe A: Antiretroviral
drug-resistant HIV‑2 infection – a new
therapeutic dilemma. Int. J. STD AIDS
17(11), 781–782 (2006).
of
129 Colson P, Henry M, Tourres C et al.:
Polymorphism and drug-selected mutations in
the protease gene of human
immunodeficiency virus type 2 from patients
living in southern France. J. Clin. Microbiol.
ro
42(2), 570–577 (2004).
130 Rodes B, Toro C, Jimenez V, Soriano V: Viral
response to antiretroviral therapy in a patient
coinfected with HIV type 1 and type 2. Clin.
rP
Infect. Dis. 41(2), e19–21 (2005).
131 Maitland D, Moyle G, Hand J et al.: Early
virologic failure in HIV‑1 infected subjects on
didanosine/tenofovir/efavirenz: 12-week
results from a randomized trial. AIDS 19(11),
1183–1188 (2005).
132 Landman R, Damond F, Gerbe J,
Brun‑Vezinet F, Yeni P, Matheron S:
Immunovirological and therapeutic follow-up
of HIV‑1/HIV‑2-dually seropositive patients.
AIDS 23(3), 426–428 (2009).
133 Damond F, Lariven S, Roquebert B et al.:
Virological and immunological response to
HAART regimen containing integrase
inhibitors in HIV‑2-infected patients. AIDS
22(5), 665–666 (2008).
134 Garrett N, Xu L, Smit E, Ferns B, El-Gadi S,
Anderson J: Raltegravir treatment response in
an HIV‑2 infected patient: a case report.
AIDS 22(9), 1091–1092 (2008).
135 Xu L, Anderson J, Ferns B et al.: Genetic
diversity of integrase (IN) sequences in
antiretroviral treatment-naive and treatment-
experienced HIV type 2 patients. AIDS Res.
Hum. Retroviruses 24(7), 1003–1007 (2008).
136 Roquebert B, Blum L, Collin G et al.:
Selection of the Q148R integrase inhibitor
resistance mutation in a failing raltegravir
containing regimen. AIDS 22(15),
2045–2046 (2008).
137 Xu L, Anderson J, Garrett N et al.: Dynamics
of raltegravir resistance profile in an HIV type
2-infected patient. AIDS Res. Hum.
Retroviruses 25(8), 843–847 (2009).
HIV Ther. (2010) 4(3)
138 Harries K, Zachariah R, Manzi M et al.:
Baseline characteristics, response to and
outcome of antiretroviral therapy
among patients with HIV‑1, HIV‑2 and
dual infection in Burkina Faso. Trans. R.
Soc. Trop. Med. Hyg. 104(2), 154–161
(2010).
n A comparison of ART response in HIV‑1,
HIV‑2 and HIV‑1/2-dual-infected patients
in Burkina Faso; represents the largest
number of dual-infected patients on ART
reported to date.
139 Sarfo FS, Bibby DF, Schwab U et al.:
Inadvertent non-nucleoside reverse
transcriptase inhibitor (NNRTI)-based
antiretroviral therapy in dual HIV‑1/2 and
HIV‑2 seropositive West Africans: a
retrospective study. J. Antimicrob. Chemother.
64(3), 667–669 (2009).
140 Roquebert B, Matheron S, Benard A et al.:
Raltegravir genetic resistance patterns in
HIV‑2 patients failing raltegravir containing
regimen. Presented at: 17th Conference on
Retroviruses and Opportunistic Infections. San
Francisco, USA, 16–19 February 2010
(Abstract 558).
141 Gottlieb GS, Eholie SP, Nkengasong JN
et al.: A call for randomized controlled trials
of antiretroviral therapy for HIV‑2 infection
in West Africa. AIDS 22(16), 2069–2072;
discussion 2073–2064 (2008).
142 Jallow S, Alabi A, Sarge-Njie R et al.:
Virological response to highly active
antiretroviral therapy in patients infected with
human immunodeficiency virus type 2
(HIV‑2) and in patients dually infected with
HIV‑1 and HIV‑2 in The Gambia and
emergence of drug-resistant variants. J. Clin.
Microbiol. 47(7), 2200–2208 (2009).
143 Arien KK, Abraha A,
Quinones-Mateu ME, Kestens L, Vanham G,
Arts EJ: The replicative fitness of primary
human immunodeficiency virus type 1
(HIV‑1) group M, HIV‑1 group O, and
HIV‑2 isolates. J. Virol. 79(14), 8979–8990
(2005).
144 White HL, Kristensen S, Coulibaly DM,
Sarro YS, Chamot E, Tounkara A: Prevalence
and predictors of HIV infection amongst
Malian students. AIDS Care 21(6), 701–707
(2009).
145 Pichard E, Guindo A, Grossetete G et al.:
[Human immunodeficiency virus (HIV)
infection in Mali]. Med. Trop. (Mars) 48(4),
345–349 (1988).
146 Peeters M, Koumare B, Mulanga C et al.:
Genetic subtypes of HIV type 1 and HIV
type 2 strains in commercial sex workers from
Bamako, Mali. AIDS Res. Hum. Retroviruses
14(1), 51–58 (1998).
future science group
 Dual infection with HIV‑1 & HIV‑2: double trouble or destructive interference?
147 Mansson F, Biague A, da Silva ZJ et al.:
Prevalence and incidence of HIV‑1 and
HIV‑2 before, during and after a civil war in
an occupational cohort in Guinea-Bissau,
West Africa. AIDS 23(12), 1575–1582
(2009).
148 O’Donovan D, Ariyoshi K, Milligan P
et al.: Maternal plasma viral RNA levels
determine marked differences in mother-to-
child transmission rates of HIV‑1 and
HIV‑2 in The Gambia. MRC/Gambia
Government/University College London
Medical School working group on mother-
child transmission of HIV. AIDS 14(4),
441–448 (2000).
149 Schim van der Loeff MF, Sarge-Njie R,
Ceesay S et al.: Regional differences in HIV
trends in The Gambia: results from sentinel
surveillance among pregnant women. AIDS
17(12), 1841–1846 (2003).
150 Pepin J, Dunn D, Gaye I et al.: HIV‑2
infection among prostitutes working in
The Gambia: association with serological
evidence of genital ulcer diseases and with
generalized lymphadenopathy. AIDS 5(1),
69–75 (1991).
151 Wilkins A, Oelman B, Pepin J et al.: Trends
in HIV‑1 and HIV‑2 infection in The
Gambia. AIDS 5(12), 1529–1530 (1991).
152 Hawkes S, West B, Wilson S, Whittle H,
Mabey D: Asymptomatic carriage of
Haemophilus ducreyi confirmed by the
ho
polymerase chain reaction. Genitourin. Med.
71(4), 224–227 (1995).
ut
A
future science group
View publication stats
153 Mabey DC, Tedder RS, Hughes AS et al.:
Human retroviral infections in The Gambia:
prevalence and clinical features. Br. Med.
J. (Clin. Res. Ed.) 296(6615), 83–86 (1988).
154 Pepin J, Quigley M, Todd J et al.: Association
between HIV‑2 infection and genital ulcer
diseases among male sexually transmitted
disease patients in The Gambia. AIDS 6(5),
489–493 (1992).
155 Schim van der Loeff MF, Awasana AA,
Sarge-Njie R et al.: Sixteen years of HIV
surveillance in a West African research clinic
reveals divergent epidemic trends of HIV‑1
and HIV‑2. Int. J. Epidemiol. 35(5),
1322–1328 (2006).
156 Langley CL, Benga-De E, Critchlow CW
et al.: HIV‑1, HIV‑2, human papillomavirus
of
infection and cervical neoplasia in high-risk
African women. AIDS 10(4), 413–417
(1996).
157 Kanki P, M’Boup S, Marlink R et al.:
ro
Prevalence and risk determinants of human
immunodeficiency virus type 2 (HIV‑2) and
human immunodeficiency virus type 1
(HIV‑1) in west African female prostitutes.
Am. J. Epidemiol. 136(7), 895–907 (1992).
rP
158 Diop OM, Pison G, Diouf I, Enel C,
Lagarde E: Incidence of HIV‑1 and HIV‑2
infections in a rural community in southern
Senegal. AIDS 14(11), 1671–1672 (2000).
159 Chang LW, Osei-Kwasi M, Boakye D et al.:
HIV‑1 and HIV‑2 seroprevalence and risk
factors among hospital outpatients in the
www.futuremedicine.com
| Review
eastern region of Ghana, West Africa.
J. Acquir. Immune Defic. Syndr. 29(5),
511–516 (2002).
160 Norrgren H, Bamba S, da Silva ZJ,
Andersson S, Koivula T, Biberfeld G: High
mortality and severe immunosuppression in
hospitalized patients with pulmonary
tuberculosis and HIV‑2 infection in
Guinea-Bissau. Scand. J. Infect. Dis. 33(6),
450–456 (2001).
161 Borget MY, Diallo K, Adje-Toure C,
Chorba T, Nkengasong JN: Virologic and
immunologic responses to antiretroviral
therapy among HIV‑1 and HIV‑2 dually
infected patients: case reports from Abidjan,
Côte d’Ivoire. J. Clin. Virol. 45(1), 72–75
(2009).
162 Holmgren B, da Silva Z, Larsen O, Vastrup P,
Andersson S, Aaby P: Dual infections with
HIV‑1, HIV‑2 and HTLV-1 are more
common in older women than in men in
Guinea-Bissau. AIDS 17(2), 241–253 (2003).
„„Website
201 UNAIDS: AIDS epidemic update (2007).
http://data.unaids.org/pub/
EPISlides/2007/2007_epiupdate_en.pdf
202 The Los Alamos HIV Database.
www.hiv.lanl.gov
19