Role of Semen in Modulating the Female Genital Tract Microenvironment – Implications for HIV Transmission

Doncel, Gustavo F.; Anderson, Sharon; Zalenskaya, Irina A.

doi:10.1111/aji.12231

Cited by 48 publications

(46 citation statements)

References 121 publications

(133 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We among others believe that semen plays an active role in modulating the efficiency of HIV-1 transmission to the female genital mucosa (FGM) [5]. Semen is a complex mixture of cells and molecules with immunoregulatory function [6].…”

Section: Introductionmentioning

confidence: 99%

“…In the last few years, a growing number of reports investigated the role of semen in HIV-1 infection leading to controversial results [5,10]. Most of these findings rely on isolated cells incubated with highly diluted seminal plasma (SP) and artificial infection settings involving exogenously activated or reporter cells, which may not adequately mimic the biology of mucosal transmission.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Seminal plasma induces inflammation and enhances HIV-1 replication in human cervical tissue explants

et al. 2017

View full text Add to dashboard Cite

The most immediate and evident effect of mucosal exposure to semen in vivo is a local release of proinflammatory mediators accompanied by an influx of leukocytes into the female genital mucosa (FGM). The implication of such response in HIV-1 transmission has never been addressed due to limitations of currently available experimental models. Using human tissue explants from the uterine cervix, we developed a system of mucosal exposure to seminal plasma (SP) that supports HIV-1 replication. Treatment of ectocervical explants with SP resulted in the upregulation of inflammatory and growth factors, including IL-6, TNF, CCL5, CCL20, CXCL1, and CXCL8, and IL1A, CSF2, IL7, PTGS2, as evaluated by measuring protein levels in explant conditioned medium (ECM) and gene expression in tissue. SP treatment was also associated with increased recruitment of monocytes and neutrophils, as observed upon incubation of peripheral blood leukocytes with ECM in a transwell system. To evaluate the impact of the SP-mediated response on local susceptibility to HIV-1, we infected ectocervical explants with the CCR5-tropic variant HIV-1BaL either in the presence of SP, or after explant pre-incubation with SP. In both experimental settings SP enhanced virus replication as evaluated by HIV-1 p24gag released in explant culture medium over time, as well as by HIV-1 DNA quantification in explants infected in the presence of SP. These results suggest that a sustained inflammatory response elicited by SP soon after coitus may promote HIV-1 transmission to the FGM. Nevertheless, ectocervical tissue explants did not support the replication of transmitted/founder HIV-1 molecular clones, regardless of SP treatment. Our system offers experimental and analytical advantages over traditional models of HIV-1 transmission for the study of SP immunoregulatory effect on the FGM, and may provide a useful platform to ultimately identify new determinants of HIV-1 infection at this site.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Seminal plasma induces inflammation and enhances HIV-1 replication in human cervical tissue explants

et al. 2017

View full text Add to dashboard Cite

show abstract

“…During in vitro evaluations of some non-ARV microbicides, such as the polyanionic gel PRO 2000, semen was shown to abrogate anti-HIV activity (21). The counteractive effect of semen on microbicides has been attributed to an activity of seminal proteins on microbicide moieties (21); the formation of amyloid fibrils that enhance HIV attachment to target cells (22); and the neutralizing effect of semen that lowers the vaginal pH, prolonging the survival of HIV virions (23)(24)(25)(26). Hence, the potencies of nAbs in ectocervical (Fig.…”

Section: Assessment Of Nab Efficacy In Vitromentioning

confidence: 99%

Broadly Neutralizing Anti-HIV Antibodies Prevent HIV Infection of Mucosal Tissue Ex Vivo

Scott

Park

Dezzutti

2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

cBroadly neutralizing monoclonal antibodies (nAbs) specific for HIV are being investigated for use in HIV prevention. Due to their ability to inhibit HIV attachment to and entry into target cells, nAbs may be suitable for use as topical HIV microbicides. As such, they would present an alternative intervention for individuals who may not benefit from using antiretroviral-based products for HIV prevention. We theorize that nAbs can inhibit viral transmission through mucosal tissue, thus reducing the incidence of HIV infection. The efficacy of the PG9, PG16, VRC01, and 4E10 antibodies was evaluated in an ex vivo human model of mucosal HIV transmission. nAbs reduced HIV transmission, causing 1.5-to 2-log 10 reductions in HIV replication in ectocervical tissues and Ϸ3-log 10 reductions in HIV replication in colonic tissues over 21 days. These antibodies demonstrated greater potency in colonic tissues, with a 50-fold higher dose being required to reduce transmission in ectocervical tissues. Importantly, nAbs retained their potency and reduced viral transmission in the presence of whole semen. No changes in tissue viability or immune activation were observed in colonic or ectocervical tissue after nAb exposure. Our data suggest that topically applied nAbs are safe and effective against HIV infection of mucosal tissue and support further development of nAbs as a topical microbicide that could be used for anal as well as vaginal protection.

show abstract

“…Semen provides a protective environment for HIV virions and some of seminal fluid peptides can enhance HIV infection in vitro 16,17,19,21–23 . Among the HIV enhancing elements in human semen, the PAP248-286-derived amyloid fibril was the first and the most extensively studied peptide fragment from prostatic acid phosphatase of semen 19 .…”

Section: Discussionmentioning

confidence: 99%

“…Higher semen levels of HIV RNA were also noted in the semen of HIV-infected subjects with low CD4 cell counts, suggesting a high risk of HIV transmission in this population 14 . In addition, semen has been reported to impair the microbicide-mediated antiviral efficacy 15 and modulate the cervicovaginal microenvironment and local immunity, likely resulting in mucosal changes that enhance susceptibility to HIV infection 16 . Further studies reported that in human semen, proteolytic peptide fragment of prostatic acid phosphatase (PAP248-286) can form amyloid fibrils, which could potently enhance HIV infection in vitro 17–19 .…”

Section: Introductionmentioning

confidence: 99%

Epigallocatechin Gallate Inhibits Macaque SEVI-Mediated Enhancement of SIV or SHIV Infection

Zhou

Guo

Liu

et al. 2017

JAIDS Journal of Acquired Immune Deficiency Syndromes

View full text Add to dashboard Cite

Background Human semen contains a factor that can enhance HIV infection up to 10^5-fold in cultures. This factor is termed SEVI (Semen-derived Enhancer of Virus Infection), which is composed of proteolytic fragments (PAP248-286) from prostatic acid phosphatase (PAP) in semen. Here, we examined whether macaque SEVI can facilitate simian immunodeficiency virus (SIV) or chimeric simian/human immunodeficiency virus (SHIV) infection. We also studied the effect of EGCG on macaque SEVI-mediated SIV or SHIV enhancement. Methods SIV or SHIV was mixed with different concentrations of macaque SEVI in the presence or absence of epigallocatechin gallate (EGCG). The mixture was added to cultures of TZM-bl cells or macaque PBMC. The effect of EGCG on macaque SEVI was measured by Congo-red staining assay, thioflavin T (ThT) fluorescence assay and visualized by a transmission electron microscope. Results We identified that there is one amino acid difference at the site of 277 between human PAP248-286 and macaque PAP248-286. Macaque SEVI significantly enhanced SIV or SHIV infection of TZM-bl cells and macaque PBMC. EGCG could block macaque SEVI-mediated enhancement of SIV or SHIV infection. Mechanistically, EGCG could degrade the formation of macaque SEVI amyloid fibrils that facilitates HIV attachment to the target cells. Conclusions The finding that macaque SEVI could enhance SIV or SHIV infection indicates the possibility to use the macaque SEVI in vivo studies with the macaque models. In addition, future studies are necessary to examine whether EGCG can be used as an effective microbicide for preventing SIV or SHIV mucosal transmission.

show abstract

Role of Semen in Modulating the Female Genital Tract Microenvironment – Implications for HIV Transmission

Abstract: Citation Doncel GF, Anderson S, Zalenskaya I. Role of semen in modulating the female genital tract microenvironment -implications for HIV transmission.

Cited by 48 publications

References 121 publications

Seminal plasma induces inflammation and enhances HIV-1 replication in human cervical tissue explants

Seminal plasma induces inflammation and enhances HIV-1 replication in human cervical tissue explants

Broadly Neutralizing Anti-HIV Antibodies Prevent HIV Infection of Mucosal Tissue Ex Vivo

Epigallocatechin Gallate Inhibits Macaque SEVI-Mediated Enhancement of SIV or SHIV Infection

Contact Info

Product

Resources

About