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of General Virology (2002), 83, 1253–1265. Printed in Great Britain

Human immunodeficiency virus type 2
Jacqueline D. Reeves and Robert W. Doms
Department of Microbiology, University of Pennsylvania, 301 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104, USA

The AIDS pandemic continues to spread unchecked in
many parts of the world, with greater than 34 million
individuals currently infected with human immunodeficiency
virus (HIV). While most infections are due to HIV type 1
(HIV-1) strains, HIV-2 represents a significant minority of
all HIV infections in some countries, such as Guinea-Bissau
and Portugal. While similar in many ways, there are important
differences between HIV-1 and HIV-2 that provide insights
into virus evolution, tropism and pathogenesis. Major differences include reduced pathogenicity of HIV-2 relative to
HIV-1, enhanced immune control of HIV-2 infection and often
some degree of CD4-independence. This review discusses the
origin of HIV-2 and its relationship to simian immunodeficiency
virus and HIV-1, its epidemiology, its pathogenic potential
and how its Env protein interacts with cell surface receptors
to mediate virus infection.

Discovery of human immunodeficiency virus
type 2 (HIV-2)
AIDS, resulting from HIV-1 infection, was first recognized
in 1981 when a common pattern of symptoms was observed
among a small number of homosexual men in the USA
(Brennan & Durack, 1981 ; Gottlieb et al., 1981). AIDS cases
were soon reported in other groups, including intravenous
drug users and haemophiliacs (CDC, 1982 ; Davis et al.,
1983 ; Masur et al., 1981). Soon after the identification of AIDS
in humans, outbreaks of wasting and severe infections were
identified in captive colonies of Asian rhesus macaques in USA
primate centres and these symptoms became known as simian
AIDS (Henrickson et al., 1983 ; Letvin et al., 1983). The sera
from these animals showed cross-reactivity to HIV-1 antigens
by Western blot (Kanki et al., 1985), which led to the
identification of a related lentivirus, termed simian immunodeficiency virus (SIV) (Daniel et al., 1985). Surprisingly, sera
from Senegalese sex workers were found to cross-react
preferentially with SIV antigens compared to HIV-1 by
Western blot, indicating exposure to an SIV-like virus (Barin et
al., 1985). Subsequently, a virus more closely related to SIV
than HIV-1 was isolated from West African AIDS patients
Author for correspondence : Jacqueline D. Reeves.
Fax j1 215 573 2883. e-mail jreeves!

from Guinea-Bissau and Cape Verde (Clavel et al., 1986). This
virus, referred to as lymphadenopathy-associated virus type 2,
is now known as HIV-2.

Origin of HIV-2 and relationship to HIV-1
HIV-2, along with HIV-1 and SIV, comprise the subgenus
‘ primate lentiviruses ’. The genomic organization of these
viruses is similar, although HIV-1 and SIV of chimpanzees
(SIVcpz) encode a vpu gene, while HIV-2 and SIV of sooty
mangabeys (SIVsm) have a vpx gene. The function of Vpx is
not clear, although it may play a role in nuclear import
(Fletcher et al., 1996) and the functions normally associated
with HIV-1 Vpr may be provided separately in HIV-2 by Vpr
(cell cycle arrest in G ) and Vpx (nuclear import) in HIV-2. Vpx
(but not Vpr) is important for efficient replication of HIV-2 in
PBMCs but not T cell lines (Park & Sodroski, 1995).
Additionally, Vpx− or Vpr− SIVs can cause AIDS, while
double mutant Vpx−\Vpr− SIVs are severely attenuated (Gibbs
et al., 1995).
Despite similar genomic organizations, there is a high
degree of genetic diversity between the primate lentiviruses,
especially in their env genes. Genetic variability between
HIV-2 strains is comparable to that within HIV-1 groups, with
up to 25 % divergence in Gag, Pol and Env (Gao et al., 1994 ;
Schulz et al., 1990 ; Zagury et al., 1988).
HIV is thought to have originated from zoonotic transmissions from SIV-infected non-human primates (Gao et al.,
1992, 1999 ; Hirsch et al., 1989). SIVs from chimpanzees cluster
phylogenetically with HIV-1 (Fig. 1) (Gao et al., 1999) ; hence,
the HIV-1 epidemic is likely to have originated from SIVcpz. In
contrast, all criteria identifying HIV-2 as a zoonosis from the
sooty mangabey (Cercocebus atys) are met : i.e. similarity in
genomic organization ; phylogenetic relatedness (Fig. 1) ;
prevalence in the natural host ; geographical overlap ; and
plausible route of transmission (Sharp et al., 1995). From
phylogenetic analysis of divergent HIV-2 strains, it appears
that there have been seven independent transmissions from
sooty mangabeys to humans, resulting in HIV-2 subtypes
A–G (Chen et al., 1997a ; Gao et al., 1994 ; Yamaguchi et al.,
2000). Only one member each of subtypes C, E, F and G, and
two members of subtype D, have been identified (reviewed by
Schim van der Loeff & Aaby, 1999) and it is thought that these
rare subtypes may be primary zoonotic infections.

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1994).. 1997a . 1992 .J.. In contrast. van der Ende. Alignment of pol gene sequences of 9-fold and 10.... raising the possibility that recombination events between HIV-1 and HIV-2 will occur. with stable prevalence rates in most countries (Remy. SIV of sooty mangabeys or macaques experimentally infected with 20fold reduced relative to HIV-1.128. Sierra Leone has a low prevalence of HIV-2.. 1994 . UNAIDS\WHO. For instance. Reeves and R.. accounting for around 10–13 % of total HIV infections and 4n5 % of AIDS cases (Soriano et al. 2000 . 1999). 1999). 1996. Mozambique and Brazil. probably due to a very low virus load in many asymptomatic individuals (Adjorlolo-Johnson et al. HIV-2 and SIV strain SIVmm . while HIV-2 is more endemic. Portugal has the highest prevalence of HIV-2 infection in Europe. 1993). The transmission of HIV-2 compared to HIV-1 is detailed elsewhere (Schim van der Loeff & Aaby. W. due to the rising prevalence of HIV-1 infection in these areas (Andersson et al. Kanki et al. Transmission Due to differences in transmission rates and virulence. Kulkarni et al. Schim van der Loeff & Aaby. the frequency of transmission is reduced. 1989 . 1999 . such as GuineaBissau. a former Portuguese colony. 27 Aug 2016 03:51:59 . Rubsamen-Waigmann et al. HIV-2 is restricted primarily to West Africa. Senegal and Guinea... A lower prevalence of 1–2 % is found in surrounding countries. HIV-1 is pandemic. sexual and vertical transmissions of HIV-2 are around 5. respectively.. with permission. but the highest diversity of HIV-2 subtypes (A. 1999). 1994 . In GuineaBissau. 1998).24. Treatment of infection HIV-2-infected individuals in Europe have been treated with anti-retroviral agents (Smith et al. around BCFE 0n02 by IP: 189. transmission and treatment Epidemiology The epicentre of HIV-1 infection is East Africa. Ishikawa et al. 2000 . 2000 . have significant numbers of HIV-2 infections (reviewed by Schim van der Loeff & Aaby. Subtype A accounts for the majority of HIV-2 infections and is the predominant genotype in Guinea-Bissau and Europe (Norrgren et al.. 1. Cavaco-Silva et al. 1986). Theoretical Biology and Biophysics Group. there is an HIV-2 prevalence of up to 8–10 % (Poulsen et al. HIV-2 appears to be transmitted by the same routes as HIV-1 . Angola. 1998 . 1996). 2000) but there Downloaded from www.microbiologyresearch... 1997 . 2000).. 1998). although the prevalence of HIV-2 is a growing concern in certain parts of Europe and in the southwestern region of India. Epidemiology.79 On: Sat. countries with past socioeconomical links with Portugal. van der Ende et al.. 1999).. Gao et al. Berry et al. D. 1997 . Doms Fig.. 1991). 1998).. including The Gambia. Briefly. Los Alamos National Laboratory) (Kuiken et al. including southwest India (Babu et al.. Soriano et al. 1993 . The prototype HIV-2 strain. E and F)... B. New Mexico . probably resulting from zoonoses from local sooty mangabeys infected with diverse strains of SIVsm (Chen et al. however. Langley et al. although the prevalence among commercial sex workers in The Gambia is as high as 28 % (Ghys et al. O’Donovan et al. The epidemiology of HIV-2 is detailed further in a review by Schim van der Loeff & Aaby (1999). Instances of dual infection (HIV-1+\HIV-2+) are occurring more frequently in HIV-2 endemic regions. 1999). with rising prevalence rates in developing countries. is a subtype A virus that was isolated from a Cape Verdian (Clavel et al. Phylogenetic relationship of primate lentiviruses. Wilkins et al. 1998 . Reproduced from Human Retroviruses and AIDS (Los Alamos. ROD. In addition to West Africa.. 2001 .. Subtype B viruses seem to have originated from the eastern parts of West Africa (Ghana and the Ivory Coast) and have occasionally been isolated in Europe (reviewed by Schim van der Loeff & Aaby.

2000 . Additionally. hence the lower virus load typically observed in HIV-2-infected individuals may be accounted for by differences in virus production (Popper et al. 1995). the reduced virus load and virulence of HIV-2 may make highly active anti-retroviral therapy extremely effective (Smith et al.. which can frequently cross-react with HIV-1 strains (Bertoletti et al. 2000 . Travers et al. virus load and rate of progression are fairly comparable between HIV-1 and HIV-2 (Berry et al.24. Disease is only associated with cross-species transmission of the viruses .... 1998). the lower plasma virus load that is usually associated with HIV-2 infection or better immune control of HIV-2 replication compared to HIV-1 (Andersson et al. while nef deletions are found infrequently in HIV-1. For example. 1996 . Soriano et al. When infection does progress. Kokkotou et al. resulting in a mortality rate estimated to be two-thirds lower than that for HIV-1 (Marlink et al.. 2000). these in vivo findings have proved controversial (Aaby et al. encephalitis was shown at autopsy to be almost restricted to individuals with HIV-2-related causes of death (18 % .. many HIV-2 strains naturally have amino acids that confer drug resistance and may thus decrease the therapeutic potential of some anti-retroviral agents (Isaka et al. 1995) and in vivo (Greenberg et al. 1998) . 1998). Higher proportions of CD8+ T cells from HIV-2infected individuals retain the ability to simultaneously produce the cytokines IL-2 and IFN.... Additionally. where they significantly reduce replication in vitro and in vivo (Piguet & Trono.. CTL responses to HIV-2 infection are reviewed further by Whittle et al. however. However. triggering the production of β chemokines (Akimoto et al..e.. Berry et al. Envelope structure and function The env genes of HIV-1 and HIV-2 encode the precursor 160 and 140 kDa glycoproteins (gp160\gp140. 2000). (1998). 1998). Witvrouw et al. 1999) and. n l 170) (Lucas et al. Whittle et al. The distribution of anti-retroviral drugs within developing countries and the development of an inexpensive vaccine remain priorities. Browning et al. It is also interesting to note that deletions within the nef gene of HIV-2 are quite common (Switzer et al... AIDS-associated Kaposi’s sarcoma occurs in around 10 % of HIV-1-infected individuals (Safai... from sooty mangabeys into humans (HIV-2) and rhesus macaques (SIVmac) or from chimpanzees into humans (HIV-1). 1996 . 1998). Whittle et al. many HIV-2-infected individuals appear not to progress to AIDS at all (Poulsen et al. 2000 . 1997 . however.. 1998 . even though high virus loads can sometimes be detected in their plasma (Desrosiers.. 2001). 1993). 1987) .. 1994 . however.. The overproduction of β chemokines by PBMCs from HIV2-infected donors can prevent infection of R5 tropic (see below) HIV-1 strains in vitro (Kokkotou et al. 2001 .. the burden of proviral DNA is similar in HIV-1 and HIV-2 infections. 1993 . Whether this is because people infected with HIV-2 generally survive longer than those infected with HIV-1 or if HIV-2 is more neurotropic\neuropathogenic than HIV-1 is unknown. in the Ivory Coast. African green monkeys and chimpanzees do not develop SIV-related disease.. The clinical features of HIV-2 infection are similar to those of HIV-1 infection (Brun-Vezinet et al. HIV-2 is generally less pathogenic. Smith et al. 1993 . van der Ende et al. Rey-Cuille et al. 1991 . Whittle et al. Dern et al. can lead to the development of drug-resistance mutations in vivo (Rodes et al. Weiss et al. n l 40). 1998). 2001 . more CD4+ T cells are capable of producing IL-2 than those from HIV-1infected individuals with equivalent CD4+ T cell counts (Sousa et al.. 1999 . 2000 . 2001 . 1998 .. 1996 .org by IP: 189. 1999). Fenyo & Putkonen. Simon et al.γ.79 On: Sat. Wiktor et al... others are active against HIV-2 (Clark et al. Norrgren et al. HIV-2-infected individuals often have a strong cytotoxic T lymphocyte (CTL) response to HIV-2.. 1995. although it is less frequent in HIV-1-infected Gambians and approximately 12fold less frequent still in HIV-2-infected Gambians (Ariyoshi et al. 2000). 1994). 2001 . 2000). Furthermore. It has been reported that HIV-2 infection can prevent\ protect (‘ immunize ’) against subsequent HIV-1 infection both in vitro (Arya & Gallo.. 1999). Rappaport et al. Likewise. HIV-2-infected individuals usually have a long clinically latent period of 10 years or more. Pathogenesis and immune response Naturally infected sooty mangabeys. 1992 . These factors may also account in part for the better immune control of HIV-2 infection compared to that of HIV-1 infection.Review : HIV-2 are no reports of large-scale clinical trials involving HIV-2infected cohorts. Robert-Guroff et al. 27 Aug 2016 03:51:59 BCFF . i. compared to HIV-1 ( 1 % . Whittle et al.. Indeed. the use of single anti-retroviral agents... Gotch et al. 1999 . 1997 . or suboptimal combination therapy. van der Ende.. 1999)... 1993 . 1998 .. 1997 .. Additionally.128. Rowland-Jones et al. Ariyoshi et al. respectively). 1997).. The clinical manifestations of HIV-2 AIDS are similar to those for HIV-1 and only minor differences in pathology resulting from HIV-2. with the correct drug combination. As for HIV-1.. Interestingly. Sera from HIV-2-infected individuals are often better at neutralizing autologous as well as heterologous virus in comparison to HIV-1+ sera and some HIV-2 antisera can crossneutralize HIV-1 strains (Bjorling et al. thus a functional Nef protein may aid evasion of host immune responses.. 1997). Simon et al. 1998 .. Nef downregulates surface expression of MHC class I molecules (Kerkau et al.... 1990 ... compared to HIV-1. Le Gall et al. Ichiyama et al.microbiologyresearch.. 1988). These precursors are cleaved by a host protease into the HIV1 120 kDa and HIV-2 125 kDa surface (SU) glycoproteins Downloaded from www. 1992). 1993 . This may be due to differences in virulence.. HIV-2 (but not HIV-1) Env protein can interact with CD8 on T cells that are non-permissive to infection. Pepin et al. 1998 . 1998).. infection have been observed.

Reeves et al. Space-filling model of HIV-2 gp120 core indicating potential residues involved in coreceptor interactions and the location of the V1/V2 and V3 loop stems... $ GPR15 (Deng et al.. 1997). 1999). 1997). used by HIV-1 strains.1. 1G9N and 1GM9) and rendered with RASMOL. 1987 . Starcich et al. However... 1997). 1998 . 1999). Chan et al.79 On: Sat. Rizzuto et al. 1997 . coreceptor binding (Fig. 1999). 1990).. Many residues in this region are conserved between HIV-1.. 2) (Rizzuto et al. 1998 ..J. 1997b)... Speck et al. Owen et al.. Structural studies indicate that the HIV-1 and SIV TM proteins are highly similar (Blacklow et al.. it is not clear if use of receptors other than CCR5 or CXCR4 is relevant in vivo.. 1997 .. 1986).. McKnight et al. 1997 . 1995 . 1998).. 1991 ... CCR8 (Rucker et al.. however..7.. However. 1998) and GPR1 (Liu et al. Thus. 1991 . with dissociation constants occurring in the nM range . Doms (gp120\gp125) and the 41 and 36 kDa transmembrane (TM) glycoproteins (gp41\gp36) for HIV-1 and HIV-2. HIV-2 strains are. 2001 . 1998). 1998 .. in contrast to Downloaded from www. 1998). 1987 . Interaction with coreceptors CD4 binding induces conformational changes in the SU subunit of Env that enable it to bind a coreceptor. 1997 . some HIV-2 strains can utilize coreceptors that are not. 1997a. In the case of HIV-1.. which enable triggering of the fusion process.. 1989 . the Env–CD4 interaction is of high affinity.. 1990). Layne et al. The interaction of HIV-2 and SIV Env proteins with CD4 may be of somewhat lower affinity. 1997 . Owen et al. Unutmaz et al. CCR4 (McKnight et al. 1997 . Lu et al. Shimizu et al.. 1998 . 2000).... 27 Aug 2016 03:51:59 . SU and TM form glycoprotein ‘ spikes ’ in the virus membrane that consist of trimers of non-covalently linked SU and TM proteins (Center et al. although relatively few virus strains have been examined carefully (Ivey-Hoyle et al. 1997 . Simmons et al. Additionally. Many HIV-2 strains can. 1996 . D. Amino acids in the V3 loop of Env can determine X4 or R5 tropism for both HIV-1 and HIV-2 strains (Choe et al. Sol et al. Weissenhorn et al... Lu et al. Moore. Some alternative coreceptors are not expressed on CD4+ cells or are expressed at levels below that needed to support virus infection (Sharron et al. McCune et al. As for HIV-1.. 2000) and US28 (Pleskoff et al. HIV and SIV TM proteins consist of an N-terminal extracellular domain. McKnight et al. including CCR1 (Guillon et al. Interaction with CD4 The Env proteins of HIV are primarily involved in binding and entry. 1997 . 1995 .. 1999). Moore. McKnight et al. Pleskoff et al. 1998).. making it likely that the HIV-2 TM subunit closely resembles these proteins. based upon existing HIV-1 gp120 core crystals (pdb accession codes 1GC1. 1997). This structure was predicted by SWISSPROT. CXCR5 (Kanbe et al. 1997). CX CR1 (Reeves et al. RDC1 (Shimizu et al.. for example.. version 2. 1997 . in general. all HIV2 strains use either CCR5 and\or CXCR4 as major coreceptors for entry into CD4+ cells (Bron et al. Cocchi et al.... Reeves and R. around 3–4 nM for the HIV-1 IIIB strain (Lasky et al. more promiscuous than HIV-1 strains in their use of by IP: 189. while that for the SIVmac SU protein is around 350 nM (Ivey-Hoyle et al. Owen et al. 1998 . In addition.. 1998 . Yang et al.. 1998 . 1990). HIV-2 and SIV strains. Reeves et al.... Owen et al. 2.. 1997 . Hill et al. Other coreceptors used by HIV-2 strains include CCR2b (Guillon et al.. As for HIV-1. indicating that these proteins likely share similar structures.. respectively (Freed et al. 1998 . Owen et al. 1998). Rucker et al. 1997 .. or are rarely.. containing a fusion peptide and two αhelical regions.. a number of HIV-2 isolates have been described that can infect cells independently of CD4 (see below) (Reeves et al. the dissociation constant of HIV-2ROD/A SU protein to CD4 is approximately 45 nM. Isaka et al.. 1986 . it is likely that CD4 binding induces similar conformational changes in HIV-2 Env. CCR3 (Bron et al. 1988).. 1997 .. For example... Predicted coreceptor-binding site on HIV-2 gp120. use a wider range of coreceptors compared to HIV-1 and may use these as efficiently as CCR5 or CXCR4 (Guillon et al. 1999 . 1997 . 1995 . CD4 binding induces the formation and\or exposure of a highly conserved domain in the bridging sheet region of the SU protein that has been shown to be important for BCFG Fig.128. 1998). APJ (Liu et al. a membrane-spanning domain and a C-terminal intracellular domain with an endocytosis\basolateral targeting signal and two amphipathic regions.. Sol et al.. Rucker et al. Nonetheless.. W. Weissenhorn et al.. 1990 . Chan et al. As for HIV-1. SU proteins interact with cellular receptors to attach virus particles to the cell surface and to induce conformational changes in both the SU and TM proteins. the SU protein of HIV-2 contains five variable (V1–V5) and five conserved domains (C1–C5). For most HIV-1 strains. b . numerous N-linked glycosylation sites and conserved disulphide bonds (Modrow et al.microbiologyresearch. 1999 . 2000 . 2000). residues in HIV-1 gp120 implicated in CD4 or coreceptor binding are highly conserved in SIV and HIV-2 (Kwong et al.. Thus. Deng et al. 1998)..24. 1996 . Willey et al. 2000). Moore.. 1998 . CD4 is the primary receptor for all HIV-2 strains.. Owen et al. STRL33 (Deng et al.

and a further two mutations conferred efficient CD4-independent infection (Reeves & Schulz. isolates can differ in their relative tropism for macrophages and human T cells lines. 1999). CCR8. 1998 . 1998 . The use of CXCR4 (X4 tropism) is characteristic of these viruses. SIV strains that can use CCR5. some HIV-2 and SIV strains are able to infect PBMCs independently of either CCR5 or CXCR4 (Chen et al. van’t Wout et al. CCR5. Li et al. 1999). 2001 .. 1999 . Even some HIV-2 strains that typically require CD4 to infect cells can be induced to infect CD4− cell lines by pretreatment with soluble CD4 (sCD4) (Clapham et al. GPR15 or STRL33 for CD4-independent infection have also been identified (Edinger et al. 1999.. These viruses typically use CCR5 as their major coreceptor and are referred to as R5 tropic. 1997). Reeves et al.. Owen et al. including CCR3.Review : HIV-2 HIV-1. 1997.. 1996 . de Roda Husman et al.. These viruses typically use both CXCR4 and CCR5 and are termed R5\X4.79 On: Sat. Additionally. 1996 . 1997. the N terminus and second extracellular loop of CXCR4 are important in mediating fusion and infection of HIV-2 ROD (Brelot et al. R5X4 viruses may precede the evolution to X4 tropism.. induce syncytia (multinucleated giant cells) and replicate to high titres relatively quickly and are termed syncytium-inducing. Kolchinsky et al.128. the importance of CCR5 for virus infection was shown by the discovery that individuals who lack CCR5 are highly resistant to virus infection (Liu et al. 27 Aug 2016 03:51:59 BCFH . 1996 ...... including receptor density. It is therefore apparent that CD4independence can be acquired by multiple mechanisms and that only a few amino acid changes are needed to confer CD4independence. many primary HIV-2 isolates exhibit some degree of CD4-independence (Reeves et al.. although a host of other factors. can also influence virus infection... CD4 binding by these strains is likely to modify the 7TMbinding site to increase the affinity of the Env–7TM interaction Downloaded from www. 1997). do not induce syncytia in infected primary T cells and replicate slowly to relatively low titres and are thus referred to as macrophage tropic. enabling direct contact with a coreceptor (Fig. 1998 . The second group consists of those that infect macrophage cultures efficiently. Simmons et al. Additionally. 1998 ... 1998). 1999). CD4-independent HIV2 variants can arise spontaneously in vitro from chronically infected T cell lines (Clapham et al. R5 virus strains are predominantly transmitted. 1992 . Potempa et al. Kolchinsky et al. primary syncytium-inducing isolates can infect macrophages via CXCR4 (Simmons et al. The third group can infect both T cell lines and macrophages and are thus referred to as dual-tropic viruses. 1988)... For HIV-1. 2001 . Only two mutations were required to confer a minimal CD4independent phenotype to ROD\B. LaBranche et al. 1992 . GPR1. 3). non-syncytium-inducing or slow\low viruses. Endres et al.. These same mutations increase the fusogenicity of the envelope protein as well as increasing the sensitivity of the envelope to undergo conformational changes induced by sCD4. 1998 . while HIV-1 infection usually requires both CD4 and a coreceptor. Thus. These viruses primarily use CXCR4 for infection of CD4− cells but can also use other 7TM receptors independently of CD4. 2000 .. Reeves & Schulz... 1998). In addition. 1996). Reeves et al. 1997b. 1997 .. Schenten et al. Virus tropism and coreceptor use in vivo While all HIV-1. 1997 .microbiologyresearch. 1998 . 1997 . 1999 . The Env determinants responsible for the CD4-independence of two HIV-2 strains (ROD\B and vcp) have been analysed in detail (Lin et al. 1999 ... Reeves et al. as only a few isolates from asymptomatic individuals predominantly use CCR5 (Guillon et al. Samson et al.. Morner et al.. 2000) and may thus drive evolution of alternative receptor use. which occurs in less than 50 % of AIDS patients (Connor et al.. 2000 ..24.. 1999).. conformation and post-entry events. Tersmette et al. a variant of the prototypic CD4-dependent HIV-2 ROD\A strain. 1997 .. Sol et al. 1999 . 2000 . 1999). Reeves et al. are the major virus population in asymptomatic individuals and usually remain present throughout the course of infection (Connor et al. Huang et al. An evolution from R5 to X4 is not obvious in HIV-2-infected individuals as many primary isolates use a range of coreceptors including both CCR5 and CXCR4 and only a limited number of X4 viruses have been isolated from symptomatic patients (Guillon et al. HIV-2 and SIV isolates infect primary CD4+ T cells. The first group consists of viruses that infect CD4+ T cell lines in vitro.. and were thus historically divided into three groups.. it is not known if R5 HIV-2 strains are largely responsible for virus transmission. 1996). 1999 . although the CD4-independence of other viruses is conferred by different regions of env (Dumonceaux et al... Zhang et al.. 1998).... CD4-independent virus infection One of the most striking differences between HIV-1 and HIV-2 strains is that.. 1999). virus tropism is largely explained by coreceptor usage. T cell tropic or rapid\high viruses. 1997 . Kokkotou et al. The fact that HIV-2 and SIV strains more readily infect CD4− cells compared to HIV-1 strains may indicate that their coreceptor-binding site is at least partially exposed in the absence of CD4. 1999).org by IP: 189.. In addition. GPR15 and STRL33 (Endres et al. Coreceptor domains that are involved in mediating HIV-2 infection are similar to those required for HIV-1. Reeves et al. 2000). 1998). 2000) implicating a potential role of at least some alternative receptor(s) for infection in vivo. Lin et al. HIV-2 infection may result in higher levels of β chemokine production compared to HIV-1 infection (Akimoto et al. For example. while only a few CD4-independent HIV-1 strains that were selected in vitro have been described (Dumonceaux et al. Simmons et al.. The CD4-independence of the HIV-1 IIIB variant 8x is mediated by mutations in similar regions of envelope as those found in ROD\B (LaBranche et al. as well as in their replication rates.

and SIV-infected astrocytes have been cultured ex vivo from infected macaques. CD4-independent HIV-2 strains that can use both CCR5 and CXCR4 to infect CD4+ cells are only able to use one of these receptors in the absence of CD4.... 1997 . 1996 . This interaction induces conformational changes in Env that allow a secondary interaction with a 7TM coreceptor to occur. However. gp120 first interacts with CD4 at the cell surface. Wiley et al. A neurovirulent SIV strain can infect CD4− brain capillary endothelial cells (BCECs) both in vitro and in vivo (Edinger et al. indicating that both HIV-2 and SIV can also infect astrocytes in vivo (Guillemin et al. Such infection is usually restrictive. however.. or to contribute extra energy to trigger fusion of virus and cell membranes. In the brain. Doms Fig. W.. 1987 . 1996). Therefore.. Stoler et al. the frequencies of infection of many CD4− cell types in vivo are unknown and there are no reports of HIV-2 tropism for CD4− cells in vivo.79 On: Sat. Nonetheless.. with structural gag and env genes poorly expressed.. CD4− astrocytes are susceptible to HIV-1 infection in vivo (Bagasra et al. further conformational changes result in fusion of viral and cellular membranes. Reeves and R. Downloaded from www. 1994 . In addition. Moses et al.128. BCFI lymphoid tissue and lungs (Epstein et al. 1994) and HIV-1 infection of BCECs has also been observed in vitro via CCR5 and in vivo (Bagasra et al. indicating that the use of CD4 enables a wider range of 7TM receptors to be exploited for infection (Reeves et al. CD4-independent HIV-2 ROD\B can productively infect astrocytes in vitro via CXCR4 (Reeves et al.24. 1994). CD4independent viruses can bypass CD4 and interact directly with a coreceptor molecule to initiate fusion. 1986). broadened cell tropism and enhanced sensitivity to neutralization. 1991 . Wiley et al. 27 Aug 2016 03:51:59 . 1998). Implications for pathogenesis While CD4+ haematopoietic cells are the major targets of HIV in vivo. Sankale et al. For CD4-dependent infection. for by IP: 189. 1994 . Ward et al. 3.microbiologyresearch.. 1996 .. D. 1999). Ward et al. Following coreceptor binding. particularly in paediatric AIDS cases (Saito et al. CD4-independent viruses have the potential to infect a broader range of cell types in vivo..... Tornatore et al. 1987 . Mankowski et al. 1999). Itescu et al.J.. such as the brain.. 1986 . Indeed. both HIV-2 and SIV strains have the potential to infect CD4-independently in vivo via an interaction with CCR5 or CXCR4. In vitro studies. 1986). 1993 . CD4-dependent and CD4-independent infection.. infection of CD4− cells has been reported in a minority of HIV-1-positive individuals. indicate that selection can occur at different sites in vivo and suggest some possible sites where CD4-independent viruses may be important. Either or both of these roles would provide HIV2 with the capacity to exploit coreceptors that otherwise do not interact with gp120 strongly enough to trigger fusion. HIV-2. The ability to infect cells in the absence of CD4 is associated with HIV-2 and SIV strains and correlates with exposed coreceptor binding sites.. coupled with the fact that viruses with distinct sequences and phenotypes can become compartmentalized in different tissues within an individual.

Kaneko. Env proteins that elicit antibodies to conserved epitopes. i... which seems to compromise or weaken the interaction of Env with CCR5. F. For the most part.128. P. F. 1993 . Monoclonal antibodies to such epitopes do interact preferentially with CD4-independent HIV-1 strains (Edwards et al. Binding to CD4 also enables a wider range of 7TM receptors to be exploited for infection (Reeves et al. sera from HIV-2-infected individuals are often broadly cross neutralizing (Bjorling et al. 1999) and may assist adaptation or switching to new coreceptors in vivo.. In effect. 462– by IP: 189.. H. Sibailly..microbiologyresearch. Biberfeld.. G. (1999).. 1998). Robert-Guroff et al. Does HIV-2 protect against HIV-1 infection? AIDS 11. G. it is heavily glycosylated and attempts to generate broadly crossreactive neutralizing antibodies have been largely unsuccessful. may prove to be better vaccine candidates. HIV-2 appears to be a mildly attenuated form of HIV-1.24. Hoffman et al.. Hashimoto. George. yet is clearly more pathogenic than SIV in its natural host. functionally important regions in Env have been identified that could be targets for neutralizing antibodies. HIV-2 is clearly less pathogenic than HIV-1 . Melbye. & Albert... 1992 .. such as the coreceptorbinding domain. Andersson. Concluding remarks HIV-2 provides an interesting contrast to HIV-1. yet are invariably far more sensitive to neutralizing antibodies and HIV-positive human serum (Edwards et al. Ekpini. & Yamamoto.. 939–940. HIV-2 has remained more restricted in its distribution. 1997) and to inhibition by RANTES (Kledal et al. J.-Y. in turn.. Hoffman et al. It will be important to determine if genetically triggered. 214–218. 2001 . Immunology 95. A. CD4. H. S. HIV-2 therefore provides an important opportunity to study immune control and pathogenesis of lentivirus infections in humans.. it is transmitted less efficiently.. H. E. A. Archives of Internal Medicine 160.. Yet.. N. 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