Part of this manuscript was presented at the International Society for Immunology in Reproduction Conference, May 29, 2013, Boston, MA, USA.
Role of Semen in Modulating the Female Genital Tract Microenvironment – Implications for HIV Transmission
Article first published online: 7 APR 2014
© 2014 The Authors. American Journal of Reproductive Immunology Published by John Wiley & Sons Ltd
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
American Journal of Reproductive Immunology
Special Issue: Sex Hormones and HIV Transmission
Volume 71, Issue 6, pages 564–574, June 2014
How to Cite
Role of semen in modulating the female genital tract microenvironment – implications for HIV transmission. Am J Reprod Immunol 2014; 71: 564–574, , .
- Issue published online: 16 MAY 2014
- Article first published online: 7 APR 2014
- Manuscript Accepted: 19 FEB 2014
- Manuscript Received: 11 DEC 2013
- US International Agency for Development. Grant Number: GPO-A-00-08-00005-00
- National Institute of Allergy and Infectious Diseases. Grant Number: Y1-AI-1756-01
- Bill and Melinda Gates Foundation. Grant Number: ID 41266
- vaginal inflammation;
- vaginal innate immunity
Semen deposition results in modulated immunity and an inflammatory response of the genital mucosa, which promotes conditions facilitating conception and pregnancy. These semen-induced alterations in the female reproductive tract can also have implications for the sexual transmission of viral infections such as HIV-1. Semen is not only a vector for HIV-1 but also a carrier for pro- and antiviral factors. Semen induces significant mucosal changes upregulating gene, and transcription factors leading to recruitment and activation of HIV target cells, stimulation of HIV replication and potentiation of Toll-like receptor responses. Although more research is needed to clearly elucidate the resulting collective effects of all these factors, semen modulation of the cervicovaginal microenvironment and immune system appears to lead, through multiple mechanisms, to mucosal changes facilitating viral entry and replication, likely resulting in enhanced susceptibility to acquire HIV-1 infection.
Role of Semen in HIV Transmission
Human seminal plasma is a complex fluid that contains multiple bioactive molecules and structures that not only provide medium for sperm transport and survival, but also induce changes in the female reproductive tract (FRT). Semen deposition results in modulated immunity and an inflammatory response of the genital mucosa, which promotes conditions that facilitate conception and pregnancy.[1, 2] These semen-induced alterations in the FRT can also have implications for the sexual transmission of viral infections such as HIV-1. Therefore, there is a pressing need to further characterize the impact of semen on the regulation of mucosal epithelial and immune cells in the FRT.
Thirty years after it was first identified, HIV still remains a major global health pandemic, with approximately 35 million people currently living with HIV worldwide. In 2012 alone, there were 2.3 million new infections and 1.6 million deaths due to HIV/AIDS worldwide. Notably, HIV is the leading cause of death and disease for women of reproductive age globally, and heterosexual transmission is the primary mode of infection in the developing world.[3, 5]
While unprotected sexual intercourse represents the primary mode of transmission for HIV-1 infection, the estimated rates per coital act are much lower than might be expected to efficiently convey the virus through heterosexual contact. The often cited probability of male-to-female transmission is approximately 1–2 infections per 1000 unprotected vaginal acts[6, 7]; however, viral transmission could be even higher than these epidemiological estimates, based on the phase of infection in the male, seminal viral load, no use of antiretrovirals, and the presence of concurrent sexually transmitted infections (STIs) in the FRT.[8-11] Heterosexual transmission of HIV-1 likely involves a complex interplay of facilitatory and inhibitory factors that mediate the risk of infection for any given sexual encounter.
The major vector for male-to-female HIV-1 transmission during receptive vaginal sex is semen. In terms of reproduction, seminal fluid was initially considered to be merely a passive conduit that allowed for spermatozoa to successfully traverse the female genital tract in order to initiate conception and pregnancy. However, following insemination, there is a rapid reaction in FRT epithelial cells that resembles an inflammatory response. This immediate and dramatic post-coital pro-inflammatory influx has been well characterized in several mammalian species, including humans,[1, 13, 14] and has been postulated to promote fertilization, conception, and pregnancy. In addition, this mucosal reaction also encompasses local cellular changes that may impact susceptibility to HIV-1 infection.[16, 17] The exact nature of seminal modulation of viral transmission across the genital mucosa remains controversial, and semen-mediated effects both promote and inhibit infection. Biologic factors of the FRT that condition acquisition of HIV infection in women include the following: alterations in epithelial integrity, immune cell recruitment and activation, inflammation, innate antimicrobial activity, adaptive immunity, mucus barrier, and microbiota. Semen may facilitate or inhibit mucosal HIV infection through multiple mechanisms, involving one or more of the above-mentioned factors.
Mechanism of Sexual Transmission of HIV
Once HIV-1 is deposited within the female genital tract, the virus must transverse the mucosal epithelium to gain access to an array of potential cellular targets. These include dendritic cells (DCs), Langerhans' cells (LCs), macrophages, and CD4+ T cells. The primary target of HIV-1 appears to be CD4+ T cells, in which productive infection occurs through sequential interaction of HIV envelope proteins with the CD4 receptor and CCR5/CXCR4 coreceptors. The initial routes of the virion transmission to the CD4+ T cell, however, have not been clearly elucidated.
The cervicovaginal epithelium displays a heterogeneous tissue architecture that likely requires HIV-1 virions to utilize multiple strategies in order to gain entry to basal compartments where viral targets are more abundant. The vagina and ectocervix are covered by a multilayered, stratified squamous epithelium, while the endocervix is lined with a single-layered columnar epithelium. Thus, the intact vaginal and ectocervical epithelium provide a much greater protective barrier to virion transmission as compared to the endocervix, but also affords an enhanced surface area for potential penetration. Furthermore, the transformation zone (the epithelial junction between squamous ectocervix and columnar endocervical) may be particularly susceptible to HIV entry, given both its unique structure and enhanced population of CD4+ T cells.[19-21] The mucosal barrier may be breached via microabrasions resulting from sexual intercourse or concurrent inflammatory conditions of the genital mucosa.[22, 23]As discussed below, the cervicovaginal epithelium not only acts as a barrier to virion entry, but it also reacts to virus interaction with secretion of immune mediators which influence the primary infection.[24, 25] Although controversial, some evidence exists indicating genital epithelial cells may transport and even become infected by HIV.
Direct productive infection of CD4+ T cells has been demonstrated in vivo, using SIV macaque models, as well as in ex vivo experiments in which epithelial sheets were exposed to HIV-1. At the same time, there is evidence accumulating that infection of CD4+ T cells occurs more efficiently when mediated by DCs present in genital mucosal and submucosal compartments.[28-30] These cells capture HIV-1 envelope proteins and allow the virus to cross the cervicovaginal epithelial barrier. The intra-epithelial processes of the LCs help convey HIV to the submucosal lymphocytes, and following productive infection of these CD4+ T cell populations; the virus is able to propagate and disseminate via lymphatic mechanisms.[31, 32]
Studies from non-human primates suggest that SIV penetrates the cervicovaginal epithelium and is able to infect a small population of cells within an hour.[30, 33] Recently, human cervical explant and in vivo macaque exposure studies using photoactivatable-labeled virions have shown that HIV-1 can readily penetrate both intact columnar and squamous epithelium; however, the cervicovaginal epithelium is highly susceptible to viral infiltration via ‘diffusive percolation’ through interstitial spaces, while HIV-1 entry is impeded at the endocervical epithelium by mucus production.
Single-genome amplification and phenotypic analysis of blood samples taken during the acute phase of infection have determined that more than 75% of heterosexual transmission of HIV-1 arises from single founder viral variant.[35, 36] Concurrent infections and inflammation appear to facilitate infection by more than one viral variant. While the exact mechanisms are not fully understood, sexual transmission of HIV-1 at the cervicovaginal mucosa requires minimal acute exposure for systemic propagation of infection.
Impact of Sexual Intercourse on FRT Microenvironment
In addition to the deposition of semen, a process that facilitates a pro-inflammatory response and expansion of regulatory T cells,[1, 38, 39] the act of intercourse itself induces transient changes in the FRT microenvironment. While consensual intercourse does not appear to alter the number of vaginal epithelial layers or subepithelial lymphocytes, mucosal microabrasions and lacerations have been observed in a majority of women by colposcopy up to 80 hrs after coitus.[22, 41] Mucosal damage and inflammation are much more common after sexual assault and, among other factors, may underlie the reported increased transmission of HIV under these circumstances.[42, 43] During sexual activity, the vagina undergoes anatomic and physiological changes. Engorgement of the vaginal wall raises pressure inside capillaries and increases blood flow, rugae increase frictional tension, and lubricative plasma transudated through the vaginal epithelium forms a film that covers the vaginal lumen. These physical changes can alter the surface area of the vagina, affecting the distribution of cervicovaginal secretions and exogenously applied microbicide, that is, HIV preventative products.[45, 46]
Sexual intercourse can also affect the microbiota of the FRT. Frequent intercourse is associated with greater fluctuation in vaginal flora. Women reporting more than five penile/vaginal acts within the past 90 days had higher quantities of hydrogen peroxide (H2O2)-producing lactobacilli, which are thought to be protective against reproductive tract infections (RTIs), including bacterial vaginosis (BV) and HIV. However, other studies have shown that the number of partners and frequency of intercourse are not associated with H2O2-producing lactobacilli colonization.[50, 51] Semen does not appear to be the driving force in impacting FRT microbiota, as there is no difference in vaginal lactobacilli species following intercourse with or without a condom. More refined detection methods, however, have demonstrated that consistent condom use results in increased expression of L. crispatus, one of the strongest H2O2-producing species.
Semen-associated Factors Modulating HIV Transmission
There is evidence that semen both enhances and impedes HIV-1 infectivity.[17, 53] Seminal plasma (SP) contains several inhibitory factors that act to suppress mucosal transmission of HIV-1. Seminal fluid and whole semen have demonstrated anti-HIV activity in vitro in T-lymphocyte cell lines. Cationic polypeptides contained in seminal plasma and reactive oxygen species produced by seminal leukocytes and spermatozoa provide intrinsic antiviral activity against HIV-1. Seminal plasma also blocks the attachment of HIV-1 to DC-SIGN, thus preventing viral transfer to CD4+ target cells in vitro.[57, 58] Similarly, SP protects target lymphocytes from HIV-1 infection by decreasing cell surface expression of CD4 and CXCR4, although CCR5 expression is increased. There is also preliminary evidence to suggest that seminal fluid is capable of increasing female genital tract epithelial monolayer integrity, thereby strengthening the physical barrier to infection as well.
While some components of seminal fluid aggregate to provide an innate defense mechanism against HIV-1 infection, there is also mounting evidence of proviral semen-mediated effects as well. It has long been known that following ejaculation, semen raises the normally acidic pH of vaginal fluid to 7.0 or higher within 30 s, and this neutralization of the vaginal lumen can persist for at least 2 hrs.[61, 62] The buffering capacity of semen may help to maintain conditions that are conducive to HIV-1 stability and infection.[63-66] HIV-1 infection can be enhanced by amyloid fibrils formed in semen by peptides, called semen-derived enhancer of viral infection (SEVI), as well as fibrils formed by semenogelin fragments. While SEVI's biologic function is not known, in vitro, these amyloid fibrils capture HIV virions and promote their attachment to CD4+ T cells.[26, 67-71] Heparan sulfate on spermatozoa also binds HIV and transmits the virus to dendritic cells. Furthermore, complement activation in seminal fluid generates C3 cleavage and augments HIV-1 infection in epithelial cells. In vaginal epithelial cells, SP induces the secretion of CCL20 and subsequent recruitment of LCs. Similarly, female genital epithelial cells treated with semen from acutely infected men produce heightened levels of pro-inflammatory cytokines, and these factors increased HIV-LTR activation in infected T cells. Seminal fluid itself is enriched with pro-inflammatory cytokines and chemokines that can contribute to enhanced HIV replication. Finally, two in vivo studies in non-human primates indicate that seminal plasma has no significant effect on transmission rate following intravaginal inoculation with SIV. However, animals were more likely to be persistently viremic following inoculation with low doses of virus in the presence of SP as compared to without.[77, 78]
Seminal Plasma and Female Genital tract Immune Response
The inflammatory response caused by SP, while being favorable for physiological reproductive functioning of FRT, that is, facilitating embryo implantation and pregnancy, may, at the same time, provide settings that modify the susceptibility of FRT to HIV-1. Inflammation and generalized immune activation are seen as conditions favoring HIV-1 sexual transmission at the cervicovaginal mucosa due to the attraction of HIV-1 target cells, increased expression of viral receptors, and alteration of epithelial barrier integrity which would facilitate viral entry.[28, 79, 80]
Several other immunologic factors are present in semen at remarkably high levels, including IL-7, TGF-β, and prostaglandins of E series (PGE).[76, 81, 82] These immune mediators have both pro- and anti-inflammatory effects. Understanding the interaction of these various immunologic factors contained in seminal plasma with the genital mucosa has important implications for determining the impact of semen on mucosal propensity to HIV-1 infection. Importantly, immunologic effects of semen are detected not only within genital mucosa, but also at more distant sites, like FRT-related draining lymph nodes, which may also impact host HIV-1 susceptibility.
SP induces cervicovaginal epithelial expression of pro-inflammatory factors
Human seminal plasma induces an array of pro-inflammatory cytokines, while downregulating innate antiviral factors like SLPI, in cervical cell lines and explants.[14, 83] Numerous genes associated with inflammation and immune response pathways are also upregulated in ectocervical tissues following unprotected coitus. Recently, post-coital upregulation of inflammation-related cytokines and chemokines including GM-CSF, IL-1α, IL-1β, CXCL1, CXCL2 (MIP-2α), CXCL3 (MIP-2β), CCL-20 (MIP-3α) as well as a key inflammatory enzyme, cyclooxygenase 2 (COX-2), was demonstrated in the human cervix by microarray analysis, in agreement with in vitro cervical cell response to SP. In our laboratory, we performed microarray gene expression analysis of vaginal epithelial cells exposed to SP in vitro and found upregulation of many inflammation-related genes.[16, 84] We also demonstrated that semen strongly potentiates vaginal epithelial TLR activation induced by their ligands. Considering that physiological levels of pro-inflammatory cytokines enhance susceptibility to HIV-1 infection fivefold to eightfold in cervical explant tissues, this heightened inflammatory response could have important ramifications for viral transmission.
SP induces CCL20, a chemokine for CCR6 receptor expressed by HIV target cells
CCL20 secretion is upregulated both in cervical[14, 38] and vaginal epithelium by seminal plasma. CCL20 is the only chemokine ligand for the CCR6 receptor, expressed by subsets of DCs, particularly precursors of LCs, and memory T cells including CD4+ Th17 T cells.[74, 86, 87] LCs, present in cervicovaginal mucosa, are among the primary targets of HIV-1/SIV.[30, 31, 88, 89] LCs are able to capture HIV-1 virions and transport them to the draining lymph nodes where the virions can be transmitted to T cells for productive infection,[88-90, 27] although there is some evidence to suggest viral particles captured by LCs are internalized and rendered incapable of infection. In women, semen-enhanced infiltration of LCs into the genital epithelium has been demonstrated. SP has been shown to induce secretion of the chemokine CCL20 in vaginal epithelial cells via NFκB signaling pathways. In vitro, secreted CCL20 promotes the recruitment of precursor LCs that are capable of being infected by X4 and R5 tropic HIV strains. Likewise, intravaginal SIV inoculation increases CCL20 expression in endocervical epithelium, and inhibition of CCL20 prevents mucosal transmission of infection in macaque models.
CCL20/CCR6 communication is involved in the recruitment of CCR6-expressing memory CD4+Th17 cells observed in diverse tissues.[91-93] CD4+Th17 cells are a subset of pro-inflammatory helper T cells that are essential in specific settings of inflammation and elicit protective immune responses to parasitic infections. These cells co-express CCR5 and are highly permissive for HIV-1 replication in vitro. CD4+Th17 cells are among the earliest HIV/SIV preferential targets and play a crucial role in HIV pathogenesis.[86, 94-97] In contrast to the significant semen-induced increase in DCs and LCs in the female genital epithelium, no or modest increases in FRT CD4+ T cell density have been detected following semen exposure.[23, 38] At the same time, due to CCL20, a small number of these highly susceptible to HIV-1 CD4+ Th 17 cells can infiltrate the mucosal epithelium or migrate to local lymph nodes. Taken together, it can be speculated that semen-enhanced CCL20 secretion may increase male-to-female HIV-1 transmission through recruitment of LC precursors and CD4+ T cells to genital tissues.
In contrast, CCL20 at relatively high concentrations has demonstrated anti-HIV-1 activity in primary uterine and fallopian tube epithelial cells, but only when the virus was incubated with CCL20 prior to infection. Although this study does not reflect the contribution of SP, it does indicate that CCL20, particularly in the upper FRT, has endogenous antimicrobial properties as well. It will be important to determine whether semen has the same potentiating effects of CCL20 secretion in these epithelial cells, and whether this ultimately plays a protective or permissive role in HIV-1 transmission.
SP contains abundant immunomodulatory mediators
In addition to inducing pro-inflammatory factors within the FRT, semen itself contains numerous factors that can modulate seminal and mucosal immune responses. They include cytokines, chemokines, growth factors, prostaglandins, and immunoglobulins.[99, 100] In several extensive studies that have assessed immunologic factors in semen, the cytokines/chemokines IL-1α, IL-7, IL-8, MIP-3α, MCP-1, MIG and IP-10, SDFβ1 and TGF-β were enriched in the semen of HIV-uninfected and HIV-infected men[81, 101, 76, 102] compared with their blood levels. In the seminal plasma of men infected with HIV, upregulation of specific subset of pro-inflammatory factors in the seminal plasma was demonstrated in several studies.[76, 82, 101] Furthermore, there is increased interaction between individual cytokines, resulting in ‘cytokine networks’ that may be less able to effectively respond to viral infection due to their heightened correlated activity. In support of this, seminal plasma from HIV-positive men in the acute phase of infection has been reported to contain much higher concentrations of an array of pro-inflammatory cytokines and chemokines, as compared to uninfected or chronically infected samples. Furthermore, endometrial epithelial cells treated with seminal plasma from these acutely HIV-infected men produced increased levels of the pro-inflammatory cytokines IL-1α, IL-6, and TNF-α, and this immunomodulatory response increased HIV-1 replication in CD4+ T lymphocytes. Thus, there appear to be qualitative and quantitative changes in semen factors following HIV-1 infection that could impact viral propagation via heterosexual transmission in the FRT.
SP is highly enriched in IL-7
Interleukin-7 (IL-7) is a key cytokine critical in maintaining T-cell homeostasis. Interactions of IL-7 and IL-7 receptor chain (IL-7Rα) are central in thymopoiesis and regulation of peripheral T cells. This homeostatic regulatory mechanism involves feedback suppression of IL7Rα expression by IL-7. Notably, IL-7 is highly abundant in the semen of fertile men (200 times its level in blood) and significantly elevated in semen of HIV-1-infected males.[81, 82] Increased IL-7 plasma levels were also observed in HIV-infected individuals.[105, 106] In a recent study, it has been demonstrated that in ex vivo CV and lymphoid tissues, IL-7, at concentrations comparable to those found in semen, stimulated proliferation and impeded apoptosis of CD4+ T cells, which resulted in enhanced HIV-1 replication. Increase in the expression of the anti-apoptotic protein Bcl2 in response to IL-7 was implicated in preserving infected CD4+ T cells.[107, 108] Taken as a whole, IL-7 appears to exert a protective effect on target memory and HIV-infected cells that may promote the establishment of a productive infection in female vaginal tract.
SP contains large amounts of TGF-β
TGF-β is a ubiquitous cytokine, and one of the key factors implicated in modulation of host defense. Three isoforms of TGF-β (TGF-β1, TGF-β2, and TGF-β3) are abundantly expressed in many tissues, with TGF-β1 being dominant in the immune system. TGF-β promotes differentiation of naïve CD4+ cells to FOXP3-expressing regulatory T cells (Treg) cells in the presence of IL-2, and to HIV-1 preferential targets, CD4+Th17 cells, in the presence of IL-6. Thus, TGF-β is involved in regulating the balance between pro-inflammatory and suppressive immune cell lineages contributing to immune homeostasis, which can be altered depending on environmental conditions, including the presence of other cytokines or prostaglandins. TGF-β, abundantly present in semen (fivefold that of serum), has been suggested to be one of the major factors related to induction of immune tolerance in FRT, mediated through the differentiation of Treg cells and suppression of NK cells.[100, 110] TGF-β also acts as a pro-inflammatory factor and induces production of GM-CSF, IL-6, and IL-8 in ectocervical immortalized cells (Ect1) in a dose-dependent manner. Microarray analysis of genes induced in Ect1 cells by TGF-β3 revealed upregulation of a number of pro-inflammatory cytokine and chemokine genes that have also been shown to be upregulated in cervical cells by SP/semen in vitro and in vivo.
Already high in healthy men, TGF-β levels are found to be moderately increased in SP during acute HIV infection and strongly increased during the chronic stage. TGF-β has long been implicated in the regulation and pathogenesis of HIV-1.[112-114] In vitro experiments have demonstrated that TGF-β may act as a suppressor or stimulator of HIV-1, including direct activation of HIV-1-LTR, depending on timing of treatment, cell type, and virus strain.[112, 115-117] It has been proposed that overexpression of TGF-β can result in alteration of its functions from protective to pathogenic ones.
The immunomodulatory/inflammatory response induced in the FRT by the semen TGF-β may affect HIV-1 susceptibility. Semen TGF-β could facilitate HIV-1 propagation by suppressing innate immune activity of NK cells and eliciting inflammatory response in FRT, including upregulation of inflammatory cytokines and promotion of differentiation of CD4+ Th17 cells. However, further work is needed to fully determine the biologic effect on the FRT mucosa of semen-derived TGF-β.
SP contains large amounts of prostaglandins of the E series (PGE)
Prostaglandins are potent immunomediators involved in numerous physiological and pathogenetic processes. PGE2, the most studied prostaglandin, is capable of modulating immune cell functions at multiple levels.[118-121] PGE2 suppresses effector functions of macrophages and neutrophils, and impairs cytotoxic capacity of CTLs and NK cells. PGE2 is involved in the activation of DCs, but suppresses their ability to attract T cells.[122, 123] In cervical explants, PGE2 inhibits release of secretory leukocyte protease inhibitor (SLPI), an anti-HIV defense factor.
The concentration of semen PGE is several orders of magnitude higher than that of serum, although there is a high interindividual variability in the semen PGE content, In our laboratory, we found that SP stimulates expression of PTGS2 (COX-2) gene in vaginal epithelial cells and identified PGE2 as the seminal factor responsible for mediating this induction. Seminal plasma has been shown to upregulate COX-2 expression in cervical adenocarcinoma cells. Importantly, COX-2 is also known to be induced in human vaginal epithelial cells in response to TLR ligands and pro-inflammatory compounds, an effect that is potentiated in the presence of SP. Enhanced mucosal expression of COX-2, induced by pro-inflammatory stimuli and further increased by semen PGE2, may have implications for HIV-1 transmission in the FRT and explain, in part, the costimulatory effect of cervicovaginal infections.
SP triggers NF-κB translocation and gene transcription
NF-κB is an inducible transcription factor that plays a crucial role in regulating innate immune responses, as well as the induction of HIV-1 gene expression. Following exposure to SP in vitro, microarray gene expression analysis of vaginal epithelial cells revealed upregulation of many inflammation-related genes.[16, 84] Functional analysis of this gene set indicated inflammatory response as the top biofunction, and NF-kB activation as a central mechanism implicated in gene dysregulation. Activated NF-kB signaling pathway is central in inflammation and a powerful component in induction of HIV-1 gene expression. NF-kB activation stimulates HIV-1 replication by directly activating the HIV-1 promoter, LTR, and by inducing synthesis and secretion of chemokines which attract and activate new HIV-1 target cells.
We have demonstrated that SP-induced COX-2 expression in vaginal cells is mediated by NFκB and MAPK signaling pathways. Activation of NFκB in VK-2 cells occurred within 30 min of treatment with SP, as evidenced by degradation of IkB-α in the cytoplasm and abrogated expression of COX-2 in the presence of NFκB pathway-specific inhibitor. Therefore, SP-induced NFκB signaling mechanisms mediate molecular changes which may enhance mucosal susceptibility to HIV-1 infection.
Taken as a whole, the role of semen in HIV transmission clearly extends beyond that of a passive transporter for cell-free and cell-associated virus. The contribution of seminal fluid to male-to-female sexual transmission remains equivocal, and the resulting collective immunomodulatory effect of these various SP factors at the mucosa is not clear. More evidence is needed to clearly elucidate whether SP complex interaction with the mucosa leads to changes mediating enhanced susceptibility to HIV infection. Studying the resulting effect of SP on HIV/SHIV infections of human cervical tissue explants and macaques represents key experiments to provide some of these missing data.
Sexual intercourse modifies the cervicovaginal microenvironment by increasing the mucosal surface, causing microabrasions, and increasing the blood flow and cervicovaginal fluids. In addition, it introduces semen. Semen is a biologically complex fluid evolutionary selected to protect spermatozoa and increases their chances of survival and egg fertilization. HIV has hijacked this mechanism and utilizes semen as its main vector. But semen is not only the most important vector of HIV in sexual transmission, it also is an active modulator of the mucosal immune system bringing pro- and anti-inflammatory factors and inducing pro- and antiviral mediators and mucosal changes. Semen contains abundant quantities of TGF-B, IL-7, and PGE, among other potent immune mediators. It induces gene expression in cervicovaginal epithelial cells and tissues leading to upregulation and activation of pro-inflammatory genes and factors such as COX-2, CCL20, IL-8, and NFkB. It also potentiates Toll-like receptor mediated responses.
Although more research is needed to clearly elucidate the resulting collective effects of all these factors, we believe that semen modulation of the cervicovaginal microenvironment and immune system leads to mucosal changes which, through multiple mechanisms, may facilitate recruitment and/or activation of HIV target cells and increased viral entry and replication, likely resulting in enhanced susceptibility to acquire HIV-1 infection.
The work of the authors has been supported by grants of the US International Agency for Development (GPO-A-00-08-00005-00), the National Institute of Allergy and Infectious Diseases (Y1-AI-1756-01), and the Bill and Melinda Gates Foundation (ID 41266). The views of the authors do not necessarily reflect those of these funding agencies.
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