REVIEW ARTICLE

Role of Semen in HIV-1 Transmission: Inhibitor or facilitator?

Gustavo F. Doncel, Theresa Joseph, Andrea R. Thurman
CONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA, USA

Keywords Sexual transmission of human immunodeficiency virus type 1 (HIV-1)

HIV transmission, inflammation, mucosal
immunity, semen, vaginal cells
Correspondence
Gustavo F. Doncel, CONRAD-Department of
Obstetrics and Gynecology, Eastern Virginia
Medical School, Norfolk, VA 23507, USA.
E-mail: DoncelGF@evms.edu
Submitted October 14, 2010;
accepted October 18, 2010.
Citation
Doncel GF, Joseph T, Thurman AR. Role of
semen in HIV-1 transmission: inhibitor or
facilitator? Am J Reprod Immunol 2011; 65:
292–301
doi:10.1111/j.1600-0897.2010.00931.x
accounts for 60-90% of new infections, especially in developing coun-
tries. During male-to-female transmission, the virus is typically depos-
ited in the vagina as cell-free and cell-associated virions carried by
semen. But semen is more than just a carrier for HIV-1. Evidence from
in vitro and in vivo studies supports both inhibitory and enhancing
effects. Intrinsic antiviral activity mediated by cationic antimicrobial
peptides, cytotoxicity, and blockage of HIV–dendritic cell interactions
are seminal plasma properties that inhibit HIV-1 infection. On the con-
trary, neutralization of vaginal acidic pH, enhanced virus–target cell
attachment by seminal amyloid fibrils, opsonization by complement
fragments, and electrostatic interactions are factors that facilitate HIV-1
infection. The end result, i.e., inhibition or enhancement of HIV muco-
sal infection, in vivo, likely depends on the summation of all these bio-
logical effects. More research is needed, especially in animal models, to
dissect the role of these factors and establish their relevance in HIV-1
transmission.

Langerhans cells and CD4+ T lymphocytes. In addi-

Mechanisms of genital mucosal infection by HIV-1
and role of semen
Sexual transmission of human immunodeficiency
virus type 1 (HIV-1) accounts for 60–90% of new
infections, especially in developing countries.1 During
male-to-female transmission, the virus is typically
deposited in the vagina as cell-free (CF) and cell-
associated (CA) virions carried by semen. The effi-
ciency of transmission is variable, ranging from 0.1
to 0.001% depending on co-existing risk factors such
as stage of disease in the male, seminal viral load,
and sexually transmitted infections (STIs) and other
cervico-vaginal (CV) infections in the female. The
surface of the CV mucosa provides a large portal of
entry for HIV-1. The virus has been shown to pene-
trate several layers from the luminal surface into the
thin gaps between squamous epithelial cells.2 This
penetration may bring the virus in direct contact
with two key cell types presumably involved in the
initial stages of mucosal infection: intraepithelial
292
tion, the virus may reach basal epithelial cells that
are susceptible to viral binding, endocytosis, or
transcytosis, or may penetrate even further, reaching
subepithelial targets, such as T cells and dendritic
cells (DCs), through breaches in the epithelium
caused by microabrasions.3,4
Utilizing single-genome amplification and mathe-
matical modeling, it has been reported in several
patient cohorts and non-human primates that most
(60–90%) mucosal infections originate from single-
variant transmissions.5,6 The small, focally infected
population is initially composed mainly of resting
CD4+ T cells lacking conventional markers of acti-
vation.7 HIV-1 expands locally in these ‘resting’
and in activated CD4+ T cells, and then dissemi-
nates, initially to the draining lymph node and sub-
sequently to secondary lymphoid organs, to
generate a systemic infection. Exposure of repro-
ductive tract epithelium to virus increases the
expression of chemokines that recruit plasmacytoid
American Journal of Reproductive Immunology 65 (2011) 292–301
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dendritic cells (pDCs).8 They in turn recruit,
through secretion of additional chemokines, more
CD4+ T cells that fuel local expansion. Interferons
and chemokines from the pDCs also suppress viral
replication, but the balance is tipped in favor of the
virus by the cells that fuel the local expansion nec-
essary for dissemination and establishment of sys-
temic infection.
Pre-existing inflammation, caused by lower genital
tract infections such as bacterial vaginosis (BV) and
trichomoniasis, also facilitates infection by thinning
and disrupting the multilayered lining, recruiting a
pool of target cells for local HIV expansion, initiating
clinical or sub-clinical inflammation, and interfering
with innate antimicrobial activity.9 Recruitment and
activation of new HIV-1 target cells increase the
chances of infection as they provide more permissive
cells expressing receptors and co-receptors for HIV.10
Furthermore, cellular products generated during
inflammation, e.g., nuclear factor-kB (NF-kB) and
IL-6, directly facilitate HIV-1 replication by interact-
ing with genetic elements controlling proviral DNA
transcription.11
Semen represents the main vector for HIV-1
transmission worldwide. It contains three major
sources of infectious virus: free virions, infected
leukocytes, and spermatozoa-associated virions. It is
difficult to separate the contribution of CF and CA
HIV-1 to sexual transmission, as sexual exposure in
humans includes both. The infectiousness of semen
is influenced by several factors including stage of
the disease and duration of infection in the male,
with viral loads peaking in the very early stages of
infection or end-stage disease.12,13 Semen viral load
typically peaks to about 4.5 ± 0.4 log10 copies ⁄ mL
after initial infection and stabilizes after approxi-
mately 16 weeks of infection.13 Other factors such
as coexisting herpes simplex virus type 2 (HSV-2)14
also increase genital shedding and seminal viral
load of HIV-1. Highly active antiretroviral therapy
(HAART) serves to decrease viral load in the blood
and to some extent in semen,15 but a non-detect-
able viral load in the serum does not guarantee
that HIV-1 will be absent from the semen. This is
in part because of the anatomical sites, which are
the source of seminal HIV-1. Anatomical features
of the male reproductive tract and the limited
access of the immune system to compartments con-
taining germ cells suggest that HIV-1 in semen
may originate from different compartments. Most
CF HIV-1 in seminal plasma arises from sites distal
American Journal of Reproductive Immunology 65 (2011) 292–301
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ROLE OF SEMEN IN HIV-1 TRANSMISSION
to the vas deferens.16 Therefore, vasectomized men
are still able to transmit HIV-1. HIV-1-infected leu-
kocytes in semen do not parallel those found in
serum and appear to arise from a genetically dis-
tinct compartment. Recent studies indicate that
HIV-1 in men without urethritis or prostatitis
comes from sources in the male genital tract,
which are distal to the prostate, further supporting
a separate viral reservoir for seminal fluid and
plasma HIV-1.
Is semen anything more than a carrier for HIV?
Unprotected sexual intercourse between discordant
couples is the most common route of HIV-1 trans-
mission.3 Despite this, it is known that the trans-
mission of HIV-1 without other cofactors is poorly
efficient. Several cofactors such as genital ulcer dis-
ease, BV,17 HSV-218 trichomoniasis9, and male cir-
cumcision19,20 have been shown to alter the
efficiency of a productive HIV-1 infection. Other
cofactors including race, age, menopausal status,
parity, and environmental exposures such as hor-
mones (e.g. contraceptive methods) and tobacco
use likely affect the susceptibility of a host to HIV-
1 infection, but less evidence exists regarding these
variables. The fact that the risk of infection is low
and highly variable suggests that several processes
are involved in sexual transmission of the virus.
At the biological level, enhancing and inhibitory
factors are present in semen and female genital
tract secretions. The summation of their effects act-
ing in concert with seminal viral load, viral fitness,
and the structural and functional state of the CV
mucosa will determine the chances for HIV-1 to
establish a productive infection. Semen itself is
clearly more than a vector for HIV-1. Seminal
factors facilitating or inhibiting viral infection
include cationic peptides with antiviral activity,
cytotoxic molecules, amyloid fibrils derived from
seminal phosphatases, complement fragments and
prostaglandin E2 (PGE2) and bioactive peptides
responsible for inducing mucosal inflammatory
reactions (Table I). All of these interacting pro-
cesses need to be considered to better understand
HIV-1 mucosal transmission and devise strategies
for prevention. The effect of semen and seminal
plasma (SP) warrants further investigation into
in vitro and in vivo models of sexual transmission
of HIV-1 to elucidate their role, relevance, and
mechanisms of action.
293
 DONCEL ET AL.

Table I Evidence for the role of semen and ⁄ or seminal plasma (SP) in the efficiency of HIV-1 male-to-female transmission

Effect

Factor Inhibitory Enhancing Reference

In vitro. Cationic polypeptides contained in SP contribute to its aggregate anti-HIV-1 activity 4 32

In vitro. SP ⁄ semen inhibited HIV-1 (RF and IIIB) infection of T-lymphocyte cell line C8166. Inhibitory 4 31
concentrations were 35- to 50-fold lower than cytotoxic concentrations
In vitro. SP contains a potent inhibitor of the attachment of HIV-1 to DC-specific intercellular 4 33
adhesion molecule 3-grabbing non-integrin. Significant inhibition was observed using SP dilutions
as high as 1:105. Inhibitor was greater than 100 kDa, heat stable and trypsin resistant
In vivo. Rhesus macaque model. Titration study to determine viral inoculum concentration and 4 36
effect of seminal plasma on the efficiency of intravaginal infection with SIV. There wasa trend
toward an inhibitory effect of SP at lower-titer viral inocula
In vitro. After ejaculation, the pH of the vaginal fluid increases to neutral or higher pH within 30 s. 4 31, 44, 46, 47
In vitro incubation of HIV-1 (RF and IIIB) in a range of buffer systems (pH = 3.5–8.0) with C8166 cells
found that HIV-1 strains were uniformly stable at pH of 5.0–8.0, with mild reduction in infectivity
(25%) at pH 4.5
In vitro. Semen-derived enhancer of virus infection (SEVI), amyloid fibrils formed by prostatic acidic 4 48, 54
phosphatase fragments, capture HIV virions and promote their attachment to HIV-1 target cells, such
as CD4+ T lymphocytes and dendritic cells. Appropriate co-receptors (CCR5, CXCR4) are required
In vitro. R5- and X4- HIV-1 strains activate complement in seminal fluid and generate C3 cleavage 4 61
fragments, which enhance infection in colorectal cell lines (HT-29)

produced by mucosal surfaces from the oral and CV

Evidence supporting an inhibitory effect of semen
on HIV transmission
Redox Activity of Seminal Plasma
It is thought that the oxidation of SP polyamines by
diamine oxidase,21 augmented by peroxidases present
in a healthy vaginal environment, produces radicals
that inactivate HIV-1. The virus, in particular the lip-
ids contained in its envelope, is highly sensitive to
oxygen radicals.22 Semen produces reactive oxygen
species,23 which can alter the infectivity of HIV. A
normal healthy vagina also contains lactobacilli-pro-
duced hydrogen peroxide (H2O2), which maintains a
low level of virucidal activity.24 In vitro studies dem-
onstrate that at concentrations where H2O2-produc-
ing lactobacilli levels are not virucidal, the addition
of peroxidase, such as myeloperoxidase or eosinophil
peroxidase and a halide (chloride, iodide, bromide,
thiocyanate), can restore anti-HIV-1 activity.25 Data
from the 1970s also support that several viruses are
inactivated by polyamine oxidation products.26–29
Natural Antiviral Activity of Semen is Attributed
to Cationic Polypeptides Contained in SP
Cationic antimicrobial polypeptides, such as secretory
leukoprotease inhibitor, defensins and lactoferrin,
294
tracts, have been identified and found to have vary-
ing levels of antibacterial and anti-HIV-1 activity.30
O’Connor et al.31 demonstrated in vitro that semen,
and specifically SP, had antiviral activity against HIV-1.
Semen showed consistent activity against HIV-1, and
the inhibitory concentration was between 35- and
50-fold lower than the cytotoxic concentration.31 In
further experiments, Martellini et al.32 demonstrated
that SP contained 52 individual cationic polypep-
tides, which contributed to its aggregate anti-HIV-1
activity, and that SP maintained anti-HIV-1 activity,
even when diluted 3200-fold. However, this phe-
nomenon was transient, as whole SP incubated
for over 24 hr exhibited a reduction in anti-HIV-1
activity.
SP Interferes with the Attachment of HIV-1 to DC-
SIGN-Positive Cells
In order for a male-to-female HIV-1 exposure to
become a productive infection, the virus must cross
an epithelial surface to interact with T lymphocytes,
macrophages, and DCs, which are the main targets of
infection. DC-specific intercellular adhesion molecule
3-grabbing non-integrin (DC-SIGN) is expressed
by DCs at mucosal surfaces and appears to be a uni-
versal pathogen receptor, which protects HIV-1 from
American Journal of Reproductive Immunology 65 (2011) 292–301
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degradation and efficiently promotes infection of T
CD4+ cells.33,34 DC projections may extend to, or
near, the luminal surface and present antigens to
lamina propria target cells. This is why genital ulcer-
ations35 or any breach of epithelial integrity, includ-
ing micro-trauma that can exist after consensual
intercourse,4 heightens the risk of HIV-1 transmis-
sion.
SP contains a potent inhibitor of the attachment
of HIV-1 to DC-SIGN, which inhibits the capture and
transmission of HIV-1 to T CD4+ cells.33 A significant
inhibition of HIV-1 capture was observed for both
HIV-1 IIIB (CXCR4) and HIV-1 BaL (CCR5) using SP
dilutions as high as 1:104.33 The effect of SP was not
related to cell cytotoxicity, as cell viability was
higher than 90% in these models.33 This group also
incubated HIV-1 with B-THP-DC-SIGN cells and
found that SP in dilutions up to 1:103 diminished
capture of HIV-1 IIIB and HIV-1 BaL to the levels
observed for DC-SIGN negative cells, while signifi-
cant levels of inhibition were observed even at SP
dilutions as great as 1:105.33 Monocytes, activated
PBMCs, and the T cell line SupT-1 (all of which do
not express DC-SIGN) were used as negative con-
trols. Capture of HIV-1 by these cell populations was
not inhibited by SP, supporting that CD4-dependent
mechanisms of HIV-1 capture are not inhibited by
SP. Using structural analysis, it was determined that
the component of SP with inhibitory effects on DC-
SIGN had a molecular weight greater than 100 kDa
and was heat stable and resistant to the action of
trypsin.33 SP, like HIV-1, can gain access to sub-epi-
thelial target cellsand decrease the efficiency of HIV-
1 transmission via DC-SIGN.
Effects of SP in Animal Models
Using a rhesus macaque model, Miller et al.36
tested the effects of SP on the efficiency of CF SIV
transmission. In general, higher viral inoculums
produced persistent viremia in monkeys, with or
without the presence of SP. At lower viral load
inoculums (e.g., 102 or 10 TCID50), the addition of
SP showed a trend toward increasing the efficiency
of persistent viremia among animals inoculated
with SIV-mac251 grown in huPBMC stock. How-
ever, this trend was not clearly demonstrated
among animals receiving SIV-mac251 grown in
rhPMBcs.36
CA virus is also believed to be an important source
of HIV-1 sexual transmission, but may be less effi-
American Journal of Reproductive Immunology 65 (2011) 292–301
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ROLE OF SEMEN IN HIV-1 TRANSMISSION
cient at crossing the CV mucosa when compared to
CF virus.37,38 Semen of treatment-naı̈ve infected
men contains a significant number of infected leuko-
cytes (from 3 · 104 to 5.6 · 107 cells ⁄ mL, between
10 000 and 80 000 HIV DNA copies ⁄ mL).39 Recently,
Salle et al.37investigated intravaginal administration
of CA SIV prepared from spleen cells obtained
directly from two cynomolgus macaques infected
with SIVmac251. This experimental design was
thought to more accurately reflect the CA HIV-1
present in semen of infected men. Inoculated maca-
ques (n = 9) were pre-treated with depot medroxy-
progesterone acetate to thin the vaginal epithelium.
The three macaques inoculated with 107 cells
became persistently infected, but persistent infection
was not detected in animals inoculated with lower
concentrations of CA SIV (4.2 · 105–3.5 · 104),
which is in agreement with previous findings.38 CA
HIV-1, such as infected leukocytes in semen, needs
to migrate and penetrate between epithelial cells to
infect underlying HIV-1 target cells. This has been
demonstrated in vitro and in vivo in a mouse
model.40 The macaque data parallel epidemiologic
evidence which shows that the efficiency of HIV-1
transmission is increased 10-fold during acute infec-
tion, when the semen viral load provided by CF and
CA virus is at its highest.41
Evidence supporting an HIV enhancing effect of
semen on HIV transmission
Neutralization of Normal Acidic Vaginal pH
The healthy vagina is colonized with lactobacilli,
which produce lactic acid and H2O2. H2O2-producing
lactobacilli have been shown to play a crucial role in
maintaining normal vaginal flora and inhibiting the
growth of pathogens.24,42,43 Lactobacillus-produced
lactic acid creates an acidic pH in the normal vagina,
which helps maintain the resident microbiome and
combat pathogens.42 CF and CA HIV-1 are rapidly
inactivated in vitro at acidic pH levels.44 O’Connor
et al.31 demonstrated that laboratory strains of HIV-1
were uniformly stable at pH of 5.0–8.0, with mild
reduction in infectivity (25%) at pH 4.5. The pH
of semen is 7.0–8.4.45 After ejaculation, semen
increases the pH of the vaginal fluid to neutral or
higher levels within 30 s, maintaining an increased
pH level for up to 2 hr.46,47 Thus, semen can facili-
tate HIV-1 infection by raising vaginal pH, allowing
CF and CA HIV-1 to survive in a less acidic vagina.
295
 DONCEL ET AL.
Semen-derived Enhancer of Virus Infection ‘SEVI’
Screening a complex peptide ⁄ protein library derived
from human seminal fluid to determine possible
inhibitors and enhancers of HIV-1 infection, Munch
et al.48 found semen-derived enhancer of virus infec-
tion (SEVI), or semen-derived enhancer of virus
infection, a term used for amyloid fibrils formed by
the abundant semen marker prostatic acidic phos-
phatase (PAP) fragments. These amyloid fibrils are
similar to amyloid fibrils associated with Alzheimer’s
disease, which have also been previously shown to
enhance HIV-1 infection.49 PAP is a protein pro-
duced by the prostatic gland and secreted in large
amounts (1–2 mg ⁄ mL) in seminal fluid.48 Elevated
levels of PAP can be detected in the vagina for up to
24 hr after sexual intercourse.50 The predominant
form of the PAP fragment in the amyloid fibrils was
a 4551-Dalton peptide, which corresponded to amino
acids 248–286 of PAP. This fragment has eight basic
residues, which make it highly cationic (isoelectric
point = 10.21), an important property for its attach-
ment effects.51,52 These amyloid fibrils appear to cap-
ture HIV virions and promote their attachment to
HIV-1 target cells, thereby enhancing the infectious-
ness of the virus by orders of magnitude.48 The posi-
tively charged SEVI fibrils bind to both target cells
and HIV-1 virions and augment infection by increas-
ing physical contact between these entities, similar
to the manner in which synthetic cationic polymers
promote retrovirus attachment to target cells.51,53
SEVI significantly enhances binding of wild-type
HIV-1 particles and virions lacking Env, although the
absolute levels of CA p24 are about 30-fold lower in
the absence of Env.48 SEVI enhances in vitro HIV
infection in a dose- and time-dependent manner,
and its effects are seen across different envelopes.54
Infection enhancement, however, appears to be
donor dependent.54 Further experiments showed
that SEVI enhanced infection with R5-, X4- and
dual-tropic HIV-1 clones. Importantly, the enhancing
effect of SEVI was most pronounced at low concen-
trations of virus, resembling conditions of sexual
HIV-1 transmission.48 In general, these authors
stated that SEVI may promote virus attachment to
genital surfaces, penetration of the mucosal barrier,
and subsequent dissemination to lymphoid organs by
increasing HIV-1 virion binding to epithelial cells
and to migrating DCs.48 This is in accordance with
confocal microscopy data that shows the presence of
seminal fluid enhances binding of virions to epithe-
296
lial cells in ex vivo CV tissue.55 Using dose ⁄
response assays, it was determined that 1–3 virions,
in the presence of SEVI, are sufficient for productive
HIV-1 infection of PBMCs.48
The effect of SEVI enhancement was tested in
hCD4 ⁄ hCCR5-transgenic rats inoculated with either
HIV-1 YU2 or SEVI-treated HIV-1.48 Tail vein inocu-
lation with SEVI-treated HIV-1 increased the cDNA
copy numbers in splenectomy extracts by fivefold.48
Further testing of SEVI in animal models is war-
ranted, as reproducibility of the enhancing effect
in vitro varies according to the laboratory and assay
conditions employed, casting doubts about the rele-
vance of this phenomenon.
Role of Electrostatic Interactions in HIV-1
Enhancing Effects of Semen
Another possible enhancing effect of semen is medi-
ated by electrostatic interaction of spermatozoa with
HIV-1 virions, involving negatively charged heparin
sulfate. This complex can transmit virus directly to
DC-SIGN on DCs.56 Once the spermatozoa are inter-
nalized by DCs, the DCs undergo phenotypic matu-
ration and produce IL-10.56 Other receptors on
spermatozoa may also be involved. Roan et al.51
hypothesized that SEVI, because of its highly cat-
ionic nature, may bind to target cells by interacting
with cell-surface heparan sulfate proteoglycans
(HSPG), naturally occurring anionic carbohydrate
polymers that are closely related in structure to hep-
arin sulfate. They hypothesized that HSPG antago-
nists would inhibit the viral enhancing effects of
SEVI.51 Surfen, a HSPG antagonist, induced a dose-
dependent inhibition of SEVI at concentrations of
6.25 lm with the maximal inhibitory plateau occur-
ring at 50–100 lm.57 Surfen appeared to directly
inhibit SEVI and not compromise the infectivity of
the virions.57
Electrostatic interactions between SP and microbi-
cides may also hamper the efficacy of HIV-1 preven-
tion products. The antiviral activity of several
anionic polymer microbicide candidates (e.g. cellu-
lose sulfate, carrageenan) was reduced 4- to 73-fold
in the presence of SP.58 The reduction in antiviral
capacity in the presence of SP may in part be
explained by electrostatic interactions between cat-
ionic SP polyamines and the polyanions of the
microbicide candidates. This reduction in the inhibi-
tory activity of polyanionic microbicides has also
been observed in clinical trials.59,60
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Opsonization by Complement Fragments Enhances
HIV Infection
Semen from HIV-1-positive individuals contains CF
HIV-1 particles and soluble complement compo-
nents.61 Opsonization with complement was previ-
ously shown to enhance HIV-1 infection of T and B
cells, monocytes and macrophages.61 Complement
receptors are expressed on the apical surface of epi-
thelial cells, DCs, and macrophages.61 Bouhlal
et al.61 showed that both R5- and X4-tropic HIV-1
strains can activate complement in seminal fluid
in vitro. They found that enhancement of HIV-1
infection in colorectal cell lines (HT-29) was comple-
ment dependent. Infection of HT-29 cells with HIV-1
that was pre-opsonized with complement (C3 and
C9) in seminal fluid resulted in an enhanced (1.5–2-
fold) rate of HIV-1 infection compared to infection of
these cells in the presence of virus alone.61 R5- and
X4- strains activate complement in seminal fluid and
generate C3 cleavage fragments (C3a ⁄ C3adesArg).61
Proinflammatory Effects of Semen
The immediate reaction of semen deposition into the
mammalian reproductive tract is a dramatic influx of
inflammatory cells.62–64 Changes in the leukocyte
population of the female reproductive tract (FRT)
after introduction of the male ejaculate have been
well documented in mice, pigs, rabbits, and
women.63,65–67 Most of these pro-inflammatory
effects in animals are attributed to the presence of
transforming growth factor (TGF)-b in SP.68,69 The
majority of TGF-b present in male SP is synthesized
in latent form and appears to be activated by plas-
min and other enzymes in the FRT.69
Women respond to semen deposition with a simi-
lar influx of leukocytes, especially to the cervix,
called leukocytic reaction. These leukocytes predomi-
nantly include neutrophils and to a lesser extent
macrophages and T lymphocytes.63,64 SP is also con-
sidered a cause of recurrent vaginitis in certain sexu-
ally active women, a condition possibly related to SP
protein allergy and associated with localized irrita-
tion and inflammation.70 The etiology of this inflam-
matory response, however, is not well understood.
The semen-induced leukocyte influx to the FRT is
believed to be mediated by chemoattracting factors
released by the epithelial lining of the FRT in
response to sperm and SP.62 Although a transient,
semen-induced inflammation of the FRT is probably
American Journal of Reproductive Immunology 65 (2011) 292–301
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ROLE OF SEMEN IN HIV-1 TRANSMISSION
necessary for a successful establishment of preg-
nancy, it also recruits and activates HIV target cells
to the portals of virus entry, thus facilitating mucosal
infection and HIV transmission.
SP induces differential expression of inflammatory
genes in human cervical and vaginal epithelial
cells.71 In ectocervical cells, these genes include IL-8,
IL-6, CSF2, CCL2, GM-CSF, and MCP-1. Our labora-
tory has demonstrated that human SP also enhances
the secretion of proinflammatory factors such as
GM-CSF, IFN-c, IL-12p70, IL-1b, IL-6, IL-2 and IL-8
by human vaginal cells (Joseph et al., manuscript in
preparation). We and Berlier et al.72 have demon-
strated that SP also induces the expression of CCL20,
a key chemotactic factor involved in recruitment
and maturation of Langerhans cells and dendritic
cells, which, together with intraepithelial T lympho-
cytes, are considered to be the first target cells for
HIV genital mucosal infection.73–75
A common gene overexpressed in pathological
conditions involving mucosal inflammation is cyclo-
oxygenase (COX)-2. Semen exposure leads to
overexpression of COX-2 in pig and mare endome-
trium.76,77 COX-2 catalyzes the rate-limiting step in
the synthesis of prostaglandins from arachidonic
acid.78 Prostaglandins are considered to be important
biological modulators of inflammation. They attract
immune cells to the area of inflammation. They also
act in an autocrine ⁄ paracrine manner to elevate
COX-2 expression.79,80 Seminal plasma contains
1000-fold higher concentration of prostaglandins,
mainly PGE2, compared to normal endometrium.81
Seminal plasma PGE2 has been reported to induce
COX-2 in immortalized human endocervical cells.82
This induction is because of the intracellular activa-
tion of cAMP pathway via PGE2 receptor subtypes,
EP2 and EP4.
Our laboratory has demonstrated that SP also
induces COX-2 in human vaginal cells (Joseph et al.,
manuscript in preparation). Furthermore, it potenti-
ates COX-2 induction by microbial products such as
bacterial lipopeptides (Fig. 1). This enhanced expres-
sion of COX-2 could be one of the main causes of
inflammation associated with STIs and CV infections.
In addition, SP has been shown to activate multi-
ple signal transduction pathways, which are involved
in inflammatory responses. In cervical cells, SP
induces the phosphorylation of extracellular signal-
regulated kinase (ERK1 ⁄ 2) via EP4 receptor.83 In
endometrial cells, SP induces the phosphorylation of
c-Src, ERK, and activation of cAMP pathway via EP2
297
 DONCEL ET AL.

the main vector for HIV-1 in male-to-female sexual

Fig. 1 Seminal plasma induces expression of cyclooxygenase (COX)-2
in human vaginal cells. Representative immunoblot showing COX-2
expression in vaginal cells induced by seminal plasma (1%) alone and
in combination with bacterial lipopeptide. Seminal plasma potentiates
COX-2 induction by the bacterial lipopeptide.
receptor.84 SP has also been shown to activate NF-
kB signaling pathway in vaginal cells. This pathway
is considered central to inflammation and is involved
in the control of numerous proinflammatory genes
including COX-2 and multiple chemokines and cyto-
kines. NF-kB activation has also been linked to the
enhancement of HIV replication.11
Summary and conclusions
The role of semen in HIV-1 transmission is defined
by a complex array of factors and processes involved
in semen, virus, and female genital tract interactions.
Semen carries CF and CA virus and is believed to be
transmission. Seminal viral load varies with multiple
factors such as stage of infection and disease in the
male, presence of reproductive tract inflammation,
and whether or not the man is on antiretroviral
therapy. However, semen is more than a carrier for
HIV. Evidence from in vitro and in vivo studies sup-
ports both inhibitory and enhancing effects (Table I
and Fig. 2). Intrinsic antiviral activity mediated by
cationic antimicrobial peptides, cytotoxicity, and
interference of HIV-DC interaction are seminal prop-
erties that inhibit HIV infection. On the opposite
side, neutralization of vaginal acidic pH increased
viral attachment by amyloid fibrils (SEVI), opsoniza-
tion by complement fragments, and recruitment and
activation of HIV target cells to mucosal portals of
virus entry are factors that facilitate HIV infection.
The end result, i.e., inhibition or enhancement of
HIV-1 mucosal infection, in vivo, depends on the
summation of all these biological effects. More
research is needed, especially in animal models, to
elucidate the role of these factors and establish their
relevance for sexual transmission of HIV-1.

Portal of
Portal of
HIV entry
HIV entry

Inflammatory
Systemic C3 effects Systemic
circulation C9 + circulation
LN
LN B
B
Opsonization by
complement

Fig. 2 Semen-associated factors enhancing or inhibiting male-to-female transmission of HIV-1. This cartoon depicts a series of semen-associated
factors inhibiting (red) or enhancing (green) cervicovaginal mucosal infection by cell-free and cell-associated HIV-1 carried by semen. Among inhib-
iting factors are semen’s intrinsic antiviral activity, leukocyte toxicity, and interference with binding of virions to DC-specific intercellular adhesion
molecule 3-grabbing nonintegrin. On the contrary, vaginal pH neutralization, enhanced HIV attachment by semen-derived enhancer of virus infec-
tion (SEVI) fibrils, HIV opsonization by complement, and induction of proinflammatory mediators would favor HIV transmission and mucosal infec-
tion. The bottom right and left insets show a cartoon of potential portals of entry for the virus. Local amplification of a small population of
founder viruses gives rise to disseminating virus that reaches the draining lymph nodes (LN) and, through blood vessels (B), systemic circulation,
determining the initial stage of an established HIV-1 infection.

American Journal of Reproductive Immunology 65 (2011) 292–301

298 ª 2010 John Wiley & Sons A/S

Acknowledgements
This work was supported by CONRAD intramural
funds (GD) from the US Agency for International
Development (grant GPO-8-00-08-00005-00) and
the Bill and Melinda Gates Foundation (grant
41266). The views of the authors do not necessarily
represent those of their funding agencies. The
authors are also grateful to Nancy Gonyea for her
assistance in the preparation of this manuscript.
References
1 UNAIDS: 09 AIDS epidemic update http://data.unaids.org/pub/
Report/2009/JC1700_Epi_Update_2009_en.pdf.
2 Hladik F, Hope TJ: HIV infection of the genital mucosa in women.
Curr HIV ⁄ AIDS Rep 2009; 6:20–28.
3 Shattock RJ, Moore JP: Inhibiting sexual transmission of HIV-1
infection. Nat Rev Microbiol 2003; 1:25–34.
4 Norvell MK, Benrubi GI, Thompson RJ: Investigation of
microtrauma after sexual intercourse. J Reprod Med 1984; 29:269–
271.
5 Stone M, Ma ZM, Genesca M, Fritts L, Blozois S, McChesney MB,
Miller CJ: Limited dissemination of pathogenic SIV after vaginal
challenge of rhesus monkeys immunized with a live, attenuated
lentivirus. Virology 2009; 392:260–270.
6 Salazar-Gonzalez JF, Salazar MG, Keele BF, Learn GH, Giorgi EE, Li
H, Decker JM, Wang S, Baalwa J, Kraus MH, Parrish NF, Shaw KS,
Guffey MB, Bar KJ, Davis KL, Ochsenbauer-Jambor C, Kappes JC,
Saag MS, Cohen MS, Mulenga J, Derdeyn CA, Allen S, Hunter E,
Markowitz M, Hraber P, Perelson AS, Bhattacharya T, Haynes BF,
Korber BT, Hahn BH, Shaw GM: Genetic identity, biological
phenotype, and evolutionary pathways of transmitted ⁄ founder
viruses in acute and early HIV-1 infection. J Exp Med 2009;
206:1273–1289.
7 Haase AT: Targeting early infection to prevent HIV-1 mucosal
transmission. Nature 2010; 464:217–223.
8 Li N, Chen Y, He W, Yi T, Zhao D, Zhang C, Lin CL, Todorov I,
Kandeel F, Forman S, Zeng D: Anti-CD3 preconditioning separates
GVL from GVHD via modulating host dendritic cell and donor T-cell
migration in recipients conditioned with TBI. Blood 2009; 113:953–
962.
9 Thurman AR, Doncel GF: Innate Immunity and Inflammatory
Response to Trichomonas vaginalis and Bacterial Vaginosis:
Relationship to HIV Acquisition. 20678168. Am J Reprod Immunol
2010; doi:10.1111/j.1600-0897.2010.00902.x. Jul 30 [Epub ahead of
print].
10 Rebbapragada A, Howe K, Wachihi C, Pettengell C, Sunderji S,
Huibner S, Ball TB, Plummer FA, Jaoko W, Kaul R: Bacterial
vaginosis in HIV-infected women induces reversible alterations in
the cervical immune environment. J Acquir Immune Defic Syndr
2008; 49:520–522.
11 Swingler S, Easton A, Morris A: Cytokine augmentation of HIV-1
LTR-driven gene expression in neural cells. AIDS Res Hum
Retroviruses 1992; 8:487–493.
12 Tachet A, Dulioust E, Salmon D, De Almeida M, Rivalland S,
Finkielsztejn L, Heard I, Jouannet P, Sicard D, Rouzioux C:
Detection and quantification of HIV-1 in semen: identification of a
American Journal of Reproductive Immunology 65 (2011) 292–301
ª 2010 John Wiley & Sons A/S
ROLE OF SEMEN IN HIV-1 TRANSMISSION
subpopulation of men at high potential risk of viral sexual
transmission. AIDS 1999; 13:823–831.
13 Pilcher CD, Joaki G, Hoffman IF, Martinson FE, Mapanje C, Stewart
PW, Powers KA, Galvin S, Chilongozi D, Gama S, Price MA, Fiscus
SA, Cohen MS: Amplified transmission of HIV-1: comparison of HIV-
1 concentrations in semen and blood during acute and chronic
infection. AIDS 2007; 21:1723–1730.
14 Lingappa JR, Baeten JM, Wald A, Hughes JP, Thomas KK, Mujugira
A, Mugo N, Bukusi EA, Cohen CR, Katabira E, Ronald A, Kiarie J,
Farquhar C, Stewart GJ, Makhema J, Essex M, Were E, Fife KH, de
Bruyn G, Gray GE, McIntyre JA, Manongi R, Kapiga S, Coetzee D,
Allen S, Inambao M, Kayitenkore K, Karita E, Kanweka W, Delany
S, Rees H, Vwalika B, Magaret AS, Wang RS, Kidoguchi L, Barnes
L, Ridzon R, Corey L, Celum C: Daily aciclovir for HIV-1 disease
progression in people dually infected with HIV-1 and herpes
simplex virus type 2: a randomised placebo-controlled trial. Lancet
2010; 375:824–833.
15 Lorello G, la Porte C, Pilon R, Zhang G, Karnauchow T, MacPherson
P: Discordance in HIV-1 viral loads and antiretroviral drug
concentrations comparing semen and blood plasma. HIV Med 2009;
10:548–554.
16 Krieger JN, Nirapathpongporn A, Chaiyaporn M, Peterson G,
Nikolaeva I, Akridge R, Ross SO, Coombs RW: Vasectomy and
human immunodeficiency virus type 1 in semen. J Urol 1998;
159:820–825. Discussion 825–826.
17 Martin HL, Richardson BA, Nyange PM, Lavreys L, Hillier SL,
Chohan B, Mandaliya K, Ndinya-Achola JO, Bwayo J, Kreiss J:
Vaginal lactobacilli, microbial flora, and risk of human
immunodeficiency virus type 1 and sexually transmitted disease
acquisition. J Infect Dis 1999; 180:1863–1868.
18 Rebbapragada A, Wachihi C, Pettengell C, Sunderji S, Huibner S,
Jaoko W, Ball B, Fowke K, Mazzulli T, Plummer FA, Kaul R:
Negative mucosal synergy between Herpes simplex type 2 and HIV
in the female genital tract. AIDS 2007; 21:589–598.
19 Bailey RC, Moses S, Parker CB, Agot K, Maclean I, Krieger JN,
Williams CF, Campbell RT, Ndinya-Achola JO: Male circumcision
for HIV prevention in young men in Kisumu, Kenya: a randomised
controlled trial. Lancet 2007; 369:643–656.
20 Gray RH, Kigozi G, Serwadda D, Makumbi F, Watya S, Nalugoda F,
Kiwanuka N, Moulton LH, Chaudhary MA, Chen MZ, Sewankambo
NK, Wabwire-Mangen F, Bacon MC, Williams CF, Opendi P,
Reynolds SJ, Laeyendecker O, Quinn TC, Wawer MJ: Male
circumcision for HIV prevention in men in Rakai, Uganda: a
randomised trial. Lancet 2007; 369:657–666.
21 Klebanoff SJ, Kazazi F: Inactivation of human immunodeficiency
virus type 1 by the amine oxidase-peroxidase system. J Clin
Microbiol 1995; 33:2054–2057.
22 Stief TW: Singlet oxygen (1O2)-oxidazable lipids in the HIV
membrane, new targets for AIDS therapy? Med Hypotheses 2003;
60:575–577.
23 Agarwal A, Prabakaran SA: Mechanism, measurement, and
prevention of oxidative stress in male reproductive physiology.
Indian J Exp Biol 2005; 43:963–974.
24 Klebanoff SJ, Hillier SL, Eschenbach DA, Waltersdorph AM: Control
of the microbial flora of the vagina by H2O2-generating lactobacilli.
J Infect Dis 1991; 164:94–100.
25 Klebanoff SJ, Coombs RW: Viricidal effect of Lactobacillus
acidophilus on human immunodeficiency virus type 1: possible
role in heterosexual transmission. J Exp Med 1991; 174:
289–292.
299
 DONCEL ET AL.
26 Katz E, Goldblum T, Bachrach U, Goldblum N: Antiviral action of
oxidized spermine: inactivation of certain animal viruses. Isr J Med
Sci 1967; 3:575–577.
27 Bachrach U, Don S: Inactivation of influenza and Newcastle disease
viruses by oxidized spermine. Isr J Med Sci 1970; 6:435–437.
28 Bachrach U, Don S: Inactivation of myxoviruses by oxidized
polyamines. J Gen Virol 1971; 11:1–9.
29 Bachrach U, Rosenkovitch E: Effect of oxidized spermine and other
aldehydes on the infectivity of vaccinia virus. Appl Microbiol 1972;
23:232–235.
30 Cole AM, Cole AL: Antimicrobial polypeptides are key anti-HIV-1
effector molecules of cervicovaginal host defense. Am J Reprod
Immunol 2008; 59:27–34.
31 O’Connor TJ, Kinchington D, Kangro HO, Jeffries DJ: The activity
of candidate virucidal agents, low pH and genital secretions against
HIV-1 in vitro. Int J STD AIDS 1995; 6:267–272.
32 Martellini JA, Cole AL, Venkataraman N, Quinn GA, Svoboda P,
Gangrade BK, Pohl J, Sorensen OE, Cole AM: Cationic polypeptides
contribute to the anti-HIV-1 activity of human seminal plasma.
FASEB J 2009; 23:3609–3618.
33 Sabatte J, Ceballos A, Raiden S, Vermeulen M, Nahmod K, Maggini
J, Salamone G, Salomon H, Amigorena S, Geffner J: Human
seminal plasma abrogates the capture and transmission of human
immunodeficiency virus type 1 to CD4+ T cells mediated by DC-
SIGN. J Virol 2007; 81:13723–13734.
34 Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van
Duijnhoven GC, Middel J, Cornelissen IL, Nottet HS, KewalRamani
VN, Littman DR, Figdor CG, van Kooyk Y: DC-SIGN, a dendritic
cell-specific HIV-1-binding protein that enhances trans-infection of
T cells. Cell 2000; 100:587–597.
35 Galvin SR, Cohen MS: The role of sexually transmitted diseases in
HIV transmission. Nat Rev Microbiol 2004; 2:33–42.
36 Miller CJ, Marthas M, Torten J, Alexander NJ, Moore JP, Doncel
GF, Hendrickx AG: Intravaginal inoculation of rhesus macaques
with cell-free simian immunodeficiency virus results in persistent or
transient viremia 1. J Virol 1994; 68:6391–6400.
37 Salle B, Brochard P, Bourry O, Mannioui A, Andrieu T, Prevot S,
Dejucq-Rainsford N, Dereuddre-Bosquet N, Le Grand R: Infection of
macaques after vaginal exposure to cell-associated simian
immunodeficiency virus. J Infect Dis 2010; 202:337–344.
38 Miller CJ: Use of the SIV ⁄ Rhesus Macaque Model of the
Heterosexual Transmission of HIV in AIDS Vaccine Research. Vaccine
Res 1992; 1:295–301.
39 Politch JA, Mayer KH, Anderson DJ: Depletion of CD4+ T cells in
semen during HIV infection and their restoration following
antiretroviral therapy. J Acquir Immune Defic Syndr 2009; 50:283–289.
40 Zacharopoulos VR, Perotti ME, Phillips DM: A role for cell migration
in the sexual transmission of HIV-1? Curr Biol 1997; 7:534–537.
41 Pilcher CD, Tien HC, Eron Jr. JJ, Vernazza PL, Leu SY, Stewart PW,
Goh LE, Cohen MS: Brief but efficient: acute HIV infection and the
sexual transmission of HIV. J Infect Dis 2004; 189:1785–1792.
42 Hawes SE, Hillier SL, Benedetti J, Stevens CE, Koutsky LA, Wolner-
Hanssen P, Holmes KK: Hydrogen peroxide-producing lactobacilli
and acquisition of vaginal infections. J Infect Dis 1996; 174:1058–
1063.
43 Yamamoto T, Zhou X, Williams CJ, Hochwalt A, Forney LJ:
Bacterial populations in the vaginas of healthy adolescent women.
J Pediatr Adolesc Gynecol 2009; 22:11–18.
44 Ongradi J, Ceccherini-Nelli L, Pistello M, Specter S, Bendinelli M:
Acid sensitivity of cell-free and cell-associated HIV-1: clinical
implications. AIDS Res Hum Retroviruses 1990; 6:1433–1436.
300
45 WHO. WHO Laboratory Manual for the Examination and Processing
of Human Semen. 5th edn, Geneva, Switzerland, WHO, 2010. ISBN
9789241547789.
46 Fox CA, Meldrum SJ, Watson BW: Continuous measurement by
radio-telemetry of vaginal pH during human coitus. J Reprod Fertil
1973; 33:69–75.
47 Wolters-Everhardt E, Dony JM, Lemmen WA, Doesburg WH, De
Pont JJ: Buffering capacity of human semen. Fertil Steril 1986;
46:114–119.
48 Munch J, Rucker E, Standker L, Adermann K, Goffinet C, Schindler
M, Wildum S, Chinnadurai R, Rajan D, Specht A, Gimenez-Gallego
G, Sanchez PC, Fowler DM, Koulov A, Kelly JW, Mothes W, Grivel
JC, Margolis L, Keppler OT, Forssmann WG, Kirchhoff F: Semen-
derived amyloid fibrils drastically enhance HIV infection. Cell 2007;
131:1059–1071.
49 Wojtowicz WM, Farzan M, Joyal JL, Carter K, Babcock GJ, Israel
DI, Sodroski J, Mirzabekov T: Stimulation of enveloped virus
infection by beta-amyloid fibrils. J Biol Chem 2002; 277:35019–
35024.
50 Collins KA, Bennett AT: Persistence of spermatozoa and prostatic
acid phosphatase in specimens from deceased individuals during
varied postmortem intervals. Am J Forensic Med Pathol 2001; 22:228–
232.
51 Roan NR, Sowinski S, Munch J, Kirchhoff F, Greene WC:
Aminoquinoline surfen inhibits the action of SEVI (semen-derived
enhancer of viral infection). J Biol Chem 2010; 285:1861–1869.
52 Roan NR, Munch J, Arhel N, Mothes W, Neidleman J, Kobayashi A,
Smith-McCune K, Kirchhoff F, Greene WC: The cationic properties
of SEVI underlie its ability to enhance human immunodeficiency
virus infection. J Virol 2009; 83:73–80.
53 Toyoshima K, Vogt PK: Enhancement and inhibition of avian
sarcoma viruses by polycations and polyanions. Virology 1969;
38:414–426.
54 Kim KA, Yolamanova M, Zirafi O, Roan NR, Staendker L,
Forssmann WG, Burgener A, Dejucq-Rainsford N, Hahn BH, Shaw
GM, Greene WC, Kirchhoff F, Munch J: Semen-mediated
enhancement of HIV infection is donor-dependent and correlates
with the levels of SEVI. Retrovirology 2010; 7:55.
55 Maher D, Wu X, Schacker T, Horbul J, Southern P: HIV binding,
penetration, and primary infection in human cervicovaginal tissue.
Proc Natl Acad Sci USA 2005; 102:11504–11509.
56 Ceballos A, Remes Lenicov F, Sabatte J, Rodriguez Rodrigues C,
Cabrini M, Jancic C, Raiden S, Donaldson M, Agustin Pasqualini Jr
R, Marin-Briggiler C, Vazquez-Levin M, Capani F, Amigorena S,
Geffner J: Spermatozoa capture HIV-1 through heparan sulfate and
efficiently transmit the virus to dendritic cells. J Exp Med 2009;
206:2717–2733.
57 Roan NR, Sowinski S, Munch J, Kirchhoff F, Greene WC:
Aminoquinoline surfen inhibits the action of SEVI (semen-derived
enhancer of viral infection). J Biol Chem 2010; 285:1861–1869.
58 Neurath AR, Strick N, Li YY: Role of seminal plasma in the anti-
HIV-1 activity of candidate microbicides. BMC Infect Dis 2006; 6:150.
59 Patel S, Hazrati E, Cheshenko N, Galen B, Yang H, Guzman E,
Wang R, Herold BC, Keller MJ: Seminal plasma reduces the
effectiveness of topical polyanionic microbicides. J Infect Dis 2007;
196:1394–1402.
60 Keller MJ, Mesquita PM, Torres NM, Cho S, Shust G, Madan RP,
Cohen HW, Petrie J, Ford T, Soto-Torres L, Profy AT, Herold BC:
Postcoital bioavailability and antiviral activity of 0.5% PRO 2000
gel: implications for future microbicide clinical trials. PLoS ONE
2010; 5:e8781.
American Journal of Reproductive Immunology 65 (2011) 292–301
ª 2010 John Wiley & Sons A/S

61 Bouhlal H, Chomont N, Haeffner-Cavaillon N, Kazatchkine MD,
Belec L, Hocini H: Opsonization of HIV-1 by semen complement
enhances infection of human epithelial cells. J Immunol 2002;
169:3301–3306.
62 Robertson SA, O’Leary S, Armstrong DT: Influence of semen on
inflammatory modulators of embryo implantation. Soc Reprod Fertil
Suppl 2006; 62:231–245.
63 Pandya IJ, Cohen J: The leukocytic reaction of the human uterine
cervix to spermatozoa. Fertil Steril 1985; 43:417–421.
64 Thompson LA, Barratt CL, Bolton AE, Cooke ID: The leukocytic
reaction of the human uterine cervix. Am J Reprod Immunol 1992;
28:85–89.
65 Lovell JW, Getty R: Fate of semen in the uterus of the sow:
histologic study of endometrium during the 27 hours after natural
service. Am J Vet Res 1968; 29:609–625.
66 Phillips DM, Mahler S: Leukocyte emigration and migration in the
vagina following mating in the rabbit. Anat Rec 1977; 189:45–59.
67 De M, Wood GW: Analysis of the number and distribution of
macrophages, lymphocytes, and granulocytes in the mouse uterus
from implantation through parturition. J Leukoc Biol 1991; 50:381–
392.
68 Tremellen KP, Seamark RF, Robertson SA: Seminal transforming
growth factor beta1 stimulates granulocyte-macrophage colony-
stimulating factor production and inflammatory cell recruitment in
the murine uterus. Biol Reprod 1998; 58:1217–1225.
69 Robertson SA, Ingman WV, O’Leary S, Sharkey DJ, Tremellen KP:
Transforming growth factor beta–a mediator of immune deviation in
seminal plasma. J Reprod Immunol 2002; 57:109–128.
70 Ludman BG: Human seminal plasma protein allergy: a diagnosis
rarely considered. J Obstet Gynecol Neonatal Nurs 1999; 28:359–363.
71 Sharkey DJ, Macpherson AM, Tremellen KP, Robertson SA: Seminal
plasma differentially regulates inflammatory cytokine gene
expression in human cervical and vaginal epithelial cells. Mol Hum
Reprod 2007; 13:491–501.
72 Berlier W, Cremel M, Hamzeh H, Levy R, Lucht F, Bourlet T,
Pozzetto B, Delezay O: Seminal plasma promotes the attraction of
Langerhans cells via the secretion of CCL20 by vaginal epithelial
cells: involvement in the sexual transmission of HIV. Hum Reprod
2006; 21:1135–1142.
73 Lore K, Larsson M: The role of dendritic cells in the pathogenesis of
HIV-1 infection. APMIS 2003; 111:776–788.
74 Cremel M, Hamzeh-Cognasse H, Genin C, Delezay O: Female
genital tract immunization: evaluation of candidate
American Journal of Reproductive Immunology 65 (2011) 292–301
ª 2010 John Wiley & Sons A/S
ROLE OF SEMEN IN HIV-1 TRANSMISSION
immunoadjuvants on epithelial cell secretion of CCL20 and
dendritic ⁄ Langerhans cell maturation. Vaccine 2006; 24:5744–5754.
75 Hladik F, Doncel GF: Preventing mucosal HIV transmission with
topical microbicides - challenges and opportunities. Antiviral Res
2010; doi:10.1016/j.antiviral.2010.09.011. [Epub ahead of print].
76 O’Leary S, Jasper MJ, Warnes GM, Armstrong DT, Robertson SA:
Seminal plasma regulates endometrial cytokine expression,
leukocyte recruitment and embryo development in the pig.
Reproduction 2004; 128:237–247.
77 Palm F, Walter I, Budik S, Kolodziejek J, Nowotny N, Aurich C:
Influence of different semen extenders and seminal plasma on PMN
migration and on expression of IL-1beta, IL-6, TNF-alpha and COX-
2 mRNA in the equine endometrium. Theriogenology 2008; 70:843–
851.
78 Smith GD, Wolf DP, Trautman KC, da Cruz e Silva EF, Greengard P,
Vijayaraghavan S: Primate sperm contain protein phosphatase 1, a
biochemical mediator of motility. Biol Reprod 1996; 54:719–727.
79 Maldve RE, Kim Y, Muga SJ, Fischer SM: Prostaglandin E(2)
regulation of cyclooxygenase expression in keratinocytes is
mediated via cyclic nucleotide-linked prostaglandin receptors.
J Lipid Res 2000; 41:873–881.
80 Munir I, Fukunaga K, Kanasaki H, Miyazaki K, Ohba T, Okamura
H, Miyamoto E: Expression of cyclooxygenase 2 by prostaglandin
E(2) in human endometrial adenocarcinoma cell line HEC-1B. Biol
Reprod 2000; 63:933–941.
81 Templeton AA, Cooper I, Kelly RW: Prostaglandin concentrations in
the semen of fertile men. J Reprod Fertil 1978; 52:147–150.
82 Sales KJ, Katz AA, Millar RP, Jabbour HN: Seminal plasma activates
cyclooxygenase-2 and prostaglandin E2 receptor expression and
signalling in cervical adenocarcinoma cells. Mol Hum Reprod 2002;
8:1065–1070.
83 Muller M, Sales KJ, Katz AA, Jabbour HN: Seminal plasma
promotes the expression of tumorigenic and angiogenic genes in
cervical adenocarcinoma cells via the E-series prostanoid 4 receptor.
Endocrinology 2006; 147:3356–3365.
84 Battersby S, Sales KJ, Williams AR, Anderson RA, Gardner S,
Jabbour HN: Seminal plasma and prostaglandin E2 up-regulate
fibroblast growth factor 2 expression in endometrial
adenocarcinoma cells via E-series prostanoid-2 receptor-mediated
transactivation of the epidermal growth factor receptor and
extracellular signal-regulated kinase pathway. Hum Reprod 2007;
22:36–44.
301