scholarly journals Matrix Metalloproteinases Expressed in Response to Bacterial Vaginosis Disrupt the Endocervical Epithelium, Increasing Transmigration of HIV

2020 ◽  
Vol 88 (4) ◽  
Author(s):  
Michelle D. Cherne ◽  
Amy L. Cole ◽  
Lisa Newberry ◽  
Mary Schmidt-Owens ◽  
Michael Deichen ◽  
...  
Keyword(s):  
Matrix Metalloproteinases ◽  
Hiv Infection ◽  
Bacterial Vaginosis ◽  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Target Cells ◽  
Barrier Dysfunction ◽  
Host Matrix ◽  
Mmp Inhibitor ◽  
Hiv 1

ABSTRACT Bacterial vaginosis (BV), a disorder of the female reproductive tract (FRT) in which a healthy Lactobacillus-dominant microflora is replaced by BV-associated bacteria (BVAB), can significantly increase the incidence of human immunodeficiency virus (HIV) acquisition. Discerning the effect of BV on the mucosal epithelium of the FRT may yield novel preventatives and therapeutics for HIV infection. Here, we investigated barrier dysfunction of the endocervix by host-derived factors, secreted in response to BV, as a potential cause of HIV infection. Using a polarized endocervical cell culture system, we determined that conditioned media (CM) from endocervical cells cocultured with BVAB (endocervical+BVAB CM), as well as cervicovaginal fluid (CVF) from women with BV, disrupted epithelial polarization. We assessed host matrix metalloproteinases (MMPs) as the BV-associated secreted factors which disrupt the endocervical epithelium. MMPs were overexpressed in endocervical+BVAB CM and CVF from women with BV and were capable of disrupting endocervical epithelial polarization. When we cocultured polarized endocervical cells with HIV-1-infected lymphocyte-derived cells, we discovered endocervical+BVAB CM and MMPs significantly increased the transmigration of virus through the epithelium, and treatment with an MMP inhibitor decreased these effects. When we examined the effect of CVF on HIV-1 transmigration through endocervical epithelium, we demonstrated that CVF samples with greater concentrations of BV-associated MMPs increased viral transmigration. Our results suggest MMPs increase HIV-1 infection by disrupting the endocervical epithelium, permitting transmigration of virus through the epithelium to infect underlying target cells.

scholarly journals Characterization of the Influence of Semen-Derived Enhancer of Virus Infection on the Interaction of HIV-1 with Female Reproductive Tract Tissues

2015 ◽  
Vol 89 (10) ◽  
pp. 5569-5580 ◽  
Author(s):  
Shannon A. Allen ◽  
Ann M. Carias ◽  
Meegan R. Anderson ◽  
Eneniziaogochukwu A. Okocha ◽  
Lorie Benning ◽  
...  
Keyword(s):  
Cell Culture ◽  
Virus Infection ◽  
Reproductive Tract ◽  
Sexual Transmission ◽  
Female Reproductive Tract ◽  
Productive Infection ◽  
Target Cells ◽  
Mucosal Transmission ◽  
Epithelial Barriers ◽  
Hiv 1

ABSTRACTThe majority of human immunodeficiency virus type 1 (HIV-1) transmission events occur in women when semen harboring infectious virus is deposited onto the mucosal barriers of the vaginal, ectocervical, and endocervical epithelia. Seminal factors such as semen-derived enhancer of virus infection (SEVI) fibrils were previously shown to greatly enhance the infectivity of HIV-1 in cell culture systems. However, when SEVI is intravaginally applied to living animals, there is no effect on vaginal transmission. To define how SEVI might function in the context of sexual transmission, we applied HIV-1 and SEVI to intact human and rhesus macaque reproductive tract tissues to determine how it influences virus interactions with these barriers. We show that SEVI binds HIV-1 and sequesters most virions to the luminal surface of the stratified squamous epithelium, significantly reducing the number of virions that penetrated the tissue. In the simple columnar epithelium, SEVI was no longer fibrillar in structure and was detached from virions but allowed significantly deeper epithelial virus penetration. These observations reveal that the action of SEVI in intact tissues is very different in the anatomical context of sexual transmission and begin to explain the lack of stimulation of infection observed in the highly relevant mucosal transmission model.IMPORTANCEThe most common mode of HIV-1 transmission in women occurs via genital exposure to the semen of HIV-infected men. A productive infection requires the virus to penetrate female reproductive tract epithelial barriers to infect underlying target cells. Certain factors identified within semen, termed semen-derived enhancers of virus infection (SEVI), have been shown to significantly enhance HIV-1 infectivity in cell culture. However, when applied to the genital tracts of living female macaques, SEVI did not enhance virus transmission. Here we show that SEVI functions very differently in the context of intact mucosal tissues. SEVI decreases HIV-1 penetration of squamous epithelial barriers in humans and macaques. At the mucus-coated columnar epithelial barrier, the HIV-1/SEVI interaction is disrupted. These observations suggest that SEVI may not play a significant stimulatory role in the efficiency of male-to-female sexual transmission of HIV.

scholarly journals Distinct Characteristics of Endometrial and Decidual Macrophages and Regulation of Their Permissivity to HIV-1 Infection by SAMHD1

2014 ◽  
Vol 89 (2) ◽  
pp. 1329-1339 ◽  
Author(s):  
Héloïse Quillay ◽  
Hicham El Costa ◽  
Romain Marlin ◽  
Marion Duriez ◽  
Claude Cannou ◽  
...  
Keyword(s):  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
The Body ◽  
Target Cells ◽  
Mucosal Protection ◽  
Protective Mechanisms ◽  
Mucosal Transmission ◽  
Uterine Mucosa ◽  
Hiv 1

ABSTRACTIn order to develop strategies to prevent HIV-1 (human immunodeficiency virus type 1) transmission, it is crucial to better characterize HIV-1 target cells in the female reproductive tract (FRT) mucosae and to identify effective innate responses. Control of HIV-1 infection in the decidua (the uterine mucosa during pregnancy) can serve as a model to study natural mucosal protection. Macrophages are the main HIV-1 target cells in the decidua. Here we report thatin vitro, macrophages and T cells are the main HIV-1 targets in the endometrium in nonpregnant women. As reported for decidual macrophages (dM), endometrial macrophages (eM) were found to have an M2-like phenotype (CD68+CD163+CD206+IL-10high). However, eM and dM may belong to different subpopulations, as they differently express certain markers and secrete different amounts of proinflammatory and anti-inflammatory cytokines. We observed strong expression of the SAMHD1 restriction factor and weak expression of its inactive form (pSAMHD1, phosphorylated at residue Thr592) in both eM and dM. Infection of macrophages from both tissues was enhanced in the presence of the viral protein Vpx, suggesting a role for SAMHD1 in the restriction of HIV-1 infection. This study and further comparisons of the decidua with FRT mucosae in nonpregnant women should help to identify mechanisms of mucosal protection against HIV-1 infection.IMPORTANCEThe female reproductive tract mucosae are major portals of HIV-1 entry into the body. The decidua (uterine mucosa during pregnancy) can serve as a model for studying natural mucosal protection against HIV-1 transmission. A comparison of target cells and innate responses in the decidua versus the endometrium in nonpregnant women could help to identify protective mechanisms. Here, we report for the first time that macrophages are one of the main HIV-1 target cells in the endometrium and that infection of macrophages from both the endometrium and the decidua is restricted by SAMHD1. These findings might have implications for the development of vaccines to prevent HIV-1 mucosal transmission.

scholarly journals Nanoparticles containing siRNA to silence CD4 and CCR5 reduce expression of these receptors and inhibit HIV-1 infection in human female reproductive tract tissue explants

2011 ◽  
Vol 3 (2) ◽  
pp. 11 ◽  
Author(s):  
Susan K. Eszterhas ◽  
Nicole O. Ilonzo ◽  
Jennifer E. Crozier ◽  
Stela Celaj ◽  
Alexandra L. Howell
Keyword(s):  
Messenger Rna ◽  
Reproductive Tract ◽  
Antiviral Effect ◽  
Female Reproductive Tract ◽  
Target Cells ◽  
Human Female ◽  
Sirna Transfection ◽  
Tissue Explants ◽  
Hiv 1

Human Immunodeficiency Virus-type 1 (HIV- 1) binds to CD4 and CCR5 receptors on target cells in the human female reproductive tract. We sought to determine whether reducing levels of messenger RNA (mRNA) transcripts that encode these receptors in female reproductive tract cells could protect mucosal tissue explants from HIV- 1 infection. Explants prepared from the endometrium, endocervix, and ectocervix of hysterectomy tissues from HIV-1 sero-negative women were exposed to nanoparticles containing CD4- and CCR5-specific short-interfering RNA (siRNA) sequences. Explants were then exposed two days later to HIV-1, and HIV-1 reverse transcripts were measured five days post-infection. Explants treated with nanoparticles containing CD4- and CCR5-specific siRNA showed reduced levels of CD4 and CCR5 transcripts, and significantly lower levels of HIV-1 reverse transcripts compared to those treated with an irrelevant siRNA. In female reproductive tract explants and in peripheral blood cell cultures, siRNA transfection induced the secretion of IFN-alpha (IFN-α), a potent antiviral cytokine. In female mice, murine-specific Cd4-siRNA nanoparticles instilled within the uterus significantly reduced murine Cd4 transcripts by day 3. Our findings demonstrate that siRNA nanoparticles reduce expression of HIV-1 infectivity receptors in human female reproductive tract tissues and also inhibit HIV-1 infection. Murine studies demonstrate that nanoparticles can penetrate the reproductive tract tissues in vivo and silence gene expression. The induction of IFN-α after siRNA transfection can potentially contribute to the antiviral effect. These findings support the therapeutic development of nanoparticles to deliver siRNA molecules to silence host cell receptors in the female reproductive tract as a novel microbicide to inhibit mucosal HIV-1 transmission.

HIV-1 infection of the female reproductive tract

2005 ◽  
Vol 2 (1) ◽  
pp. 35-38 ◽  
Author(s):  
Alexandra L. Howell ◽  
Susana N. Asin ◽  
Grant R. Yeaman ◽  
Charles R. Wira
Keyword(s):  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Hiv 1

scholarly journals Vitamin D Status Impacts Genital Mucosal Immunity and Markers of HIV-1 Susceptibility in Women

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3176
Author(s):  
Sharon M. Anderson ◽  
Andrea R. Thurman ◽  
Neelima Chandra ◽  
Suzanne S. Jackson ◽  
Susana Asin ◽  
...  
Keyword(s):  
Vitamin D ◽  
Reproductive Tract ◽  
Serum Vitamin ◽  
Female Reproductive Tract ◽  
High Dose ◽  
Vitamin D Status ◽  
Serum Vitamin D ◽  
Vitamin D Levels ◽  
Hiv 1

While vitamin D insufficiency is known to impact a multitude of health outcomes, including HIV-1, little is known about the role of vitamin D-mediated immune regulation in the female reproductive tract (FRT). We performed a pilot clinical study of 20 women with circulating 25(OH)D levels <62.5 nmol/L. Participants were randomized into either weekly or daily high-dose oral vitamin D supplementation groups. In addition to serum vitamin D levels, genital mucosal endpoints, including soluble mediators, immune cell populations, gene expression, and ex vivo HIV-1 infection, were assessed. While systemic vitamin D levels showed a significant increase following supplementation, these changes translated into modest effects on the cervicovaginal factors studied. Paradoxically, post-supplementation vitamin D levels were decreased in cervicovaginal fluids. Given the strong correlation between vitamin D status and HIV-1 infection and the widespread nature of vitamin D deficiency, further understanding of the role of vitamin D immunoregulation in the female reproductive tract is important.

Nuclear progesterone receptor isoforms and their functions in the female reproductive tract

2011 ◽  
Vol 14 (1) ◽  
pp. 149-158 ◽  
Author(s):  
R. Rękawiecki ◽  
M. Kowalik ◽  
J. Kotwica
Keyword(s):  
Progesterone Receptor ◽  
Receptor Antagonist ◽  
Reproductive System ◽  
Reproductive Tract ◽  
Physiological Effect ◽  
Female Reproductive Tract ◽  
Target Cells ◽  
Progesterone Receptor Isoforms ◽  
Receptor Isoforms ◽  
Nuclear Progesterone Receptor

Nuclear progesterone receptor isoforms and their functions in the female reproductive tract Progesterone (P4), which is produced by the corpus luteum (CL), creates proper conditions for the embryo implantation, its development, and ensures proper conditions for the duration of pregnancy. Besides the non-genomic activity of P4 on target cells, its main physiological effect is caused through genomic action by the progesterone nuclear receptor (PGR). This nuclear progesterone receptor occurs in two specific isoforms, PGRA and PGRB. PGRA isoform acts as an inhibitor of transcriptional action of PGRB. The inactive receptor is connected with chaperone proteins and attachment of P4 causes disconnection of chaperones and unveiling of DNA binding domain (DBD). After receptor dimerization in the cells' nucleus and interaction with hormone response element (HRE), the receptor coactivators are connected and transcription is initiated. The ratio of these isoforms changes during the estrous cycle and reflects the different levels of P4 effect on the reproductive system. Both isoforms, PGRA and PGRB, also show a different response to the P4 receptor antagonist activity. Connection of the antagonist to PGRA can block PGRB, but acting through the PGRB isoform, P4 receptor antagonist may undergo conversion to a strongly receptor agonist. A third isoform, PGRC, has also been revealed. This isoform is the shortest and does not have transcriptional activity. Alternative splicing and insertion of additional exons may lead to the formation of different PGR isoforms. This paper summarizes the available data on the progesterone receptor isoforms and its regulatory action within the female reproductive system.

scholarly journals Effects of Tenofovir on Cytokines and Nucleotidases in HIV-1 Target Cells and the Mucosal Tissue Environment in the Female Reproductive Tract

2014 ◽  
Vol 58 (11) ◽  
pp. 6444-6453 ◽  
Author(s):  
Nabanita Biswas ◽  
Marta Rodriguez-Garcia ◽  
Zheng Shen ◽  
Sarah G. Crist ◽  
Jack E. Bodwell ◽  
...  
Keyword(s):  
T Cells ◽  
Biological Activity ◽  
Epithelial Cells ◽  
Hiv Infection ◽  
Proinflammatory Cytokines ◽  
Reproductive Tract ◽  
Biological Activities ◽  
Female Reproductive Tract ◽  
Immune Protection ◽  
Tnf Α

ABSTRACTTenofovir (TFV) is a reverse transcriptase inhibitor used in microbicide preexposure prophylaxis trials to prevent HIV infection. Recognizing that changes in cytokine/chemokine secretion and nucleotidase biological activity can influence female reproductive tract (FRT) immune protection against HIV infection, we tested the hypothesis that TFV regulates immune protection in the FRT. Epithelial cells, fibroblasts, CD4+T cells, and CD14+cells were isolated from the endometrium (Em), endocervix (Cx), and ectocervix (Ecx) following hysterectomy. The levels of proinflammatory cytokines (macrophage inflammatory protein 3α [MIP-3α], interleukin 8 [IL-8], and tumor necrosis factor alpha [TNF-α]), the expression levels of specific nucleotidases, and nucleotidase biological activities were analyzed in the presence or absence of TFV. TFV influenced mRNA and/or protein cytokines and nucleotidases in a cell- and site-specific manner. TFV significantly enhanced IL-8 and TNF-α secretion by epithelial cells from the Em and Ecx but not from the Cx. In contrast, in response to TFV, IL-8 secretion was significantly decreased in Em and Cx fibroblasts but increased with fibroblasts from the Ecx. When incubated with CD4+T cells from the FRT, TFV increased IL-8 (Em and Ecx) and TNF-α (Cx and Ecx) secretion levels. Moreover, when incubated with Em CD14+cells, TFV significantly increased MIP-3α, IL-8, and TNF-α secretion levels relative to those of the controls. In contrast, nucleotidase biological activities were significantly decreased by TFV in epithelial (Cx) and CD4+T cells (Em) but increased in fibroblasts (Em). Our findings indicate that TFV modulates proinflammatory cytokines, nucleotidase gene expression, and nucleotidase biological activity in epithelial cells, fibroblasts, CD4+T cells, and CD14+cells at distinct sites within the FRT.

scholarly journals Interactions between HIV-1 and Mucosal Cells in the Female Reproductive Tract

2014 ◽  
Vol 71 (6) ◽  
pp. 608-617 ◽  
Author(s):  
Ruizhong Shen ◽  
Holly E. Richter ◽  
Phillip D. Smith
Keyword(s):  
Reproductive Tract ◽  
Female Reproductive Tract ◽  
Mucosal Cells ◽  
Hiv 1
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