Productive HIV-1 infection of human cervical tissue ex vivo is associated with the secretory phase of the menstrual cycle

Saba, Elisa; Origoni, Massimo; Taccagni, Gianluca; Ferrari, Davide; Doglioni, Claudio; Nava, Alice; Lisco, Andrea; Grivel, Jean‐Charles; Margolis, Leonid; Poli, Guido

doi:10.1038/mi.2013.2

Cited by 73 publications

(79 citation statements)

References 50 publications

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“…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. This is consistent with a recent ex vivo study (34) in which the authors showed no significant upregulation of ␤-defensins, SLPI, or proinflammatory cytokines in the follicular phase. However, they concluded that tissues from the luteal phase had a better capacity to support HIV-1 infection than those from the follicular phase, suggesting the presence of other innate factors in the follicular phase that might thwart infection.…”

Section: Discussionsupporting

confidence: 81%

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: 81%

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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“…ϩ T cell population differences during the menstrual cycle with increased levels during menstruation (51), while others did not find increased CD4 ϩ T cell numbers in cervical explant tissues collected from the luteal phase or in progesterone-based contraceptive users (10,50). Although cell populations were not assessed in our study, our data suggested that neutrophil and CD4 ϩ T cell signatures were associated with the luteal phase by GSEA.…”

Section: Discussioncontrasting

confidence: 44%

“…Although still a topic of great debate there is a growing body of evidence that both endogenous and exogenous ovarian hormones, including estradiol and progesterone, are associated with increased HIV acquisition in women (3)(4)(5)(6)(7). Studies of nonhuman primates have shown that SHIV infection occurs more frequently during the progesteronedominant luteal phase of the menstrual cycle (8,9), and recent in vitro explant cultures of human cervical tissue have also shown that HIV infects explants collected during the luteal phase more productively than those collected during the follicular phase (10). Furthermore, progestins, which are synthetic progesterone derivatives commonly used in injectable hormonal contraceptives, have been shown to increase HIV acquisition risk by as much as 1.5-to 2.0-fold based on the latest meta-analysis (7,11).…”

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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“…16 At the time coinciding with ovulation, Wira and colleagues have identified a potential 'window of vulnerability' during the progesterone-dominant luteal phase for optimal viral infection. 17,18 Through analysis of multiple immunologic parameters, they identified this 7-to 10-day 19 showed in a recent study utilizing cervical tissue explants that HIV infection was associated with the luteal phase. White and colleagues found that cytotoxic activity in the upper reproductive tract was present during the follicular phase of the cycle prior to ovulation, but was absent in the consequent luteal phase.…”

Section: Impact Of the Menstrual Cycle On Hiv Susceptibilitymentioning

confidence: 99%

Anatomic and Hormonal Changes in the Female Reproductive Tract Immune Environment during the Life Cycle: Implications for HIV/STI Prevention Research

Venkatesh

Cu‐Uvin

2014

American J Rep Immunol

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Productive HIV-1 infection of human cervical tissue ex vivo is associated with the secretory phase of the menstrual cycle

Cited by 73 publications

References 50 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

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

Anatomic and Hormonal Changes in the Female Reproductive Tract Immune Environment during the Life Cycle: Implications for HIV/STI Prevention Research

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