Mucosal Serpin A1 and A3 Levels in <scp>HIV</scp> Highly Exposed Sero‐Negative Women are Affected by the Menstrual Cycle and Hormonal Contraceptives but are Independent of Epidemiological Confounders

Rahman, Syeda; Rabbani, Rasheda; Wachihi, Charles; Kimani, Joshua; Plummer, Francis A.; Ball, T. Blake; Burgener, Adam

doi:10.1111/aji.12014

Cited by 21 publications

(16 citation statements)

References 34 publications

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“…Overexpressed proteins in these individuals included many serpins (31), several of which were also overexpressed in the follicular phase in our study, as determined by both proteomic and genomic analyses, consistent with earlier findings (32). Serpins are reported to possess anti-inflammatory properties (33) and are important players in mucosal defense against HIV (32), especially in the eclipse phase (27). However, it is noteworthy that not all serine protease inhibitors we tested in this study (including SLPI and trappin-2) showed significantly different expression in the two menstrual phases.…”

Section: Discussionsupporting

confidence: 92%

“…It is intriguing to note that apoliprotein A-I (Apo A-I) was one of the abundantly expressed proteins (31) in the cervicovaginal mucosa of highly exposed seronegative (HESN) sex workers. Overexpressed proteins in these individuals included many serpins (31), several of which were also overexpressed in the follicular phase in our study, as determined by both proteomic and genomic analyses, consistent with earlier findings (32). Serpins are reported to possess anti-inflammatory properties (33) and are important players in mucosal defense against HIV (32), especially in the eclipse phase (27).…”

Section: Discussionsupporting

confidence: 90%

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Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach

Vishwanathan

Burgener

Bosinger

et al. 2015

J Virol

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Our earlier studies with pig-tailed macaques demonstrated various simian-human immunodeficiency virus (SHIV) susceptibilities during the menstrual cycle, likely caused by cyclic variations in immune responses in the female genital tract. There is concern that high-dose, long-lasting, injectable progestin-based contraception could mimic the high-progesterone luteal phase and predispose women to human immunodeficiency type 1 (HIV-1) acquisition and transmission. In this study, we adopted a systems biology approach employing proteomics (tandem mass spectrometry), transcriptomics (RNA microarray hybridization), and other specific protein assays (enzyme-linked immunosorbent assays and multiplex chemokine and cytokine measurements) to characterize the effects of hormonal changes on the expression of innate factors and secreted proteins in the macaque vagina. Several antiviral factors and pathways (including acute-phase response signaling and complement system) were overexpressed in the follicular phase. Conversely, during the luteal phase there were factors overexpressed (including moesins, syndecans, and integrins, among others) that could play direct or indirect roles in enhancing HIV-1 infection. Thus, our study showed that specific pathways and proteins or genes might work in tandem to regulate innate immunity, thus fostering further investigation and future design of approaches to help counter HIV-1 acquisition in the female genital tract. IMPORTANCEHIV infection in women is poorly understood. High levels of the hormone progesterone may make women more vulnerable to infection. This could be the case during the menstrual cycle, when using hormone-based birth control, or during pregnancy. The biological basis for increased HIV vulnerability is not known. We used an animal model with high risk for infection during periods of high progesterone. Genital secretions and tissues during the menstrual cycle were studied. Our goal was to identify biological factors upregulated at high progesterone levels, and we indeed show an upregulation of genes and proteins which enhance the ability of HIV to infect when progesterone is high. In contrast, during low-progesterone periods, we found more HIV inhibitory factors. This study contributes to our understanding of mechanisms that may regulate HIV infection in females under hormonal influences. Such knowledge is needed for the development of novel prevention strategies. F emale acquisition of human immunodeficiency virus type 1 (HIV-1) is not an efficient process, and transmission events are estimated to occur at frequencies of 1/100 to 1/1,000 exposures (1; reviewed in reference 2). Despite this, the heterosexual route is the predominant mode of HIV-1 transmission worldwide (3), and the development of strategies to reduce male-to-female vaginal transmission rates remains a priority. Animal studies have demonstrated that the time between vaginal exposure and virus detection in draining lymph nodes is as little as 1 to 3 days. There is a small window of early protection whe...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach

Vishwanathan

Burgener

Bosinger

et al. 2015

J Virol

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“…Others, using a proteomic approach, have shown a significant difference in serpin A1 levels in the CVL based on menstrual cycle phase among highly exposed seronegative women. 63 In addition, proteomic data support that CV epithelial adhesion proteins and antiproteases were reduced, and leukocyte recruitment and extravasation proteins are elevated in the CVL of healthy HIV-negative women during the LUT phase, which may support reduced CV epithelial defenses in the LUT phase. 64 The two clinical studies reported here have several strengths, foremost being that we screened participants to exclude factors such as RTIs and other medical comorbidities, which may confound endpoints when using explants or samples obtained from a wide variety of donors undergoing indicated surgery.…”

Section: No Differences In Vaginal Ph or Nugent Score Between Fol Andmentioning

confidence: 83%

Comparison of Follicular and Luteal Phase Mucosal Markers of HIV Susceptibility in Healthy Women

Thurman

Chandra

Yousefieh

et al. 2016

AIDS Research and Human Retroviruses

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The purpose of this study was to evaluate differences in vaginal immune cell populations, vaginal tissue gene expression, antimicrobial activity of the cervicovaginal (CV) lavage (CVL), vaginal flora, and p24 antigen production from CV tissues after ex vivo human immunodeficiency virus (HIV) infection between follicular (FOL) and luteal (LUT) phases of the menstrual cycle. CV tissue biopsies, CV secretions, and blood samples were obtained as part of two longitudinal clinical trials of healthy women (CONRAD D11-119 and A12-124 studies). Participants (n = 39) were HIV-seronegative women not using exogenous hormone supplementation, with normal menstrual cycles, who were screened to exclude sexually transmitted and reproductive tract infections. Serum levels of estradiol and progesterone were significantly higher in the LUT versus the FOL phase of the menstrual cycle. Controlling for race, reported contraceptive use/sexual practices, and clinical trial, we found no differences in vaginal tissue immune cell populations and activation status, transcriptomes, inhibition of HIV, herpes simplex virus type 2 and Escherichia coli by the CVL, vaginal pH or Nugent score, or production of p24 antigen after ex vivo infection by HIV-1 BaL between CV samples obtained in the FOL phase versus the LUT phase of the menstrual cycle. There were no significant correlations between serum estradiol and progesterone levels and CV endpoints. The hypothesis that the LUT phase of the menstrual cycle represents a more vulnerable stage for mucosal infection with HIV was not supported by data from samples obtained from the lower genital tract (ectocervix and vagina) from these two clinical trials.

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“…In contrast, anti-inflammatory factors such as antiproteases have been associated with reduced acquisition among highly exposed sex workers (18,23). Several of these antiviral factors have shown a relationship with the menstrual cycle and the corresponding ovarian hormones dominant during each phase, including an elevation of serpins during the follicular phase (24), and a reduction of SLPI and defensins during the ovulatory/early luteal phase (25,26). Although there is a body of evidence supporting an association between progesterone and menstrual cycle phase with altered host mucosal innate immunity, a comprehensive analysis has never been performed and represents a major gap in knowledge.…”

mentioning

confidence: 99%

Molecular Signatures of Immune Activation and Epithelial Barrier Remodeling Are Enhanced during the Luteal Phase of the Menstrual Cycle: Implications for HIV Susceptibility

Birse

Arnold

Novak

et al. 2015

J Virol

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The variable infectivity and transmissibility of HIV/SHIV has been recently associated with the menstrual cycle, with particular susceptibility observed during the luteal phase in nonhuman primate models and ex vivo human explant cultures, but the mechanism is poorly understood. Here, we performed an unbiased, mass spectrometry-based proteomic analysis to better understand the mucosal immunological processes underpinning this observed susceptibility to HIV infection. Cervicovaginal lavage samples (n ‫؍‬ 19) were collected, characterized as follicular or luteal phase using days since last menstrual period, and analyzed by tandem mass spectrometry. Biological insights from these data were gained using a spectrum of computational methods, including hierarchical clustering, pathway analysis, gene set enrichment analysis, and partial least-squares discriminant analysis with LASSO feature selection. Of the 384 proteins identified, 43 were differentially abundant between phases (P < 0.05, >2-fold change). Cell-cell adhesion proteins and antiproteases were reduced, and leukocyte recruitment (interleukin-8 pathway, P ‫؍‬ 1.41E-5) and extravasation proteins (P ‫؍‬ 5.62E-4) were elevated during the luteal phase. LASSO/PLSDA identified a minimal profile of 18 proteins that best distinguished the luteal phase. This profile included cytoskeletal elements and proteases known to be involved in cellular movement. Gene set enrichment analysis associated CD4؉ T cell and neutrophil gene set signatures with the luteal phase (P < 0.05). Taken together, our findings indicate a strong association between proteins involved in tissue remodeling and leukocyte infiltration with the luteal phase, which may represent potential hormone-associated mechanisms of increased susceptibility to HIV. IMPORTANCERecent studies have discovered an enhanced susceptibility to HIV infection during the progesterone-dominant luteal phase of the menstrual cycle. However, the mechanism responsible for this enhanced susceptibility has not yet been determined. Understanding the source of this vulnerability will be important for designing efficacious HIV prevention technologies for women. Furthermore, these findings may also be extrapolated to better understand the impact of exogenous hormone application, such as the use of hormonal contraceptives, on HIV acquisition risk. Hormonal contraceptives are the most widely used contraceptive method in sub-Saharan Africa, the most HIV-burdened area of the world. For this reason, research conducted to better understand how hormones impact host immunity and susceptibility factors important for HIV infection is a global health priority. The global HIV incidence rates for women remain high, so much so that every minute a young woman becomes infected with HIV (1). With infection rates twice as high for women aged 15 to 24 compared to their age-matched male counterparts, it is clear that young women are more susceptible to HIV infection (1, 2). Understanding biological contributors to HIV risk in women is therefore impo...

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Mucosal Serpin A1 and A3 Levels in HIV Highly Exposed Sero‐Negative Women are Affected by the Menstrual Cycle and Hormonal Contraceptives but are Independent of Epidemiological Confounders

Abstract: This study shows the relationship of serpins to the menstrual cycle and hormonal contraceptives, as well as their independence to epidemiological sexual confounders. This information provides a broader understanding of innate components of the mucosal immune system in women.

Cited by 21 publications

References 34 publications

Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach

Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach

Comparison of Follicular and Luteal Phase Mucosal Markers of HIV Susceptibility in Healthy Women

Molecular Signatures of Immune Activation and Epithelial Barrier Remodeling Are Enhanced during the Luteal Phase of the Menstrual Cycle: Implications for HIV Susceptibility

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