The Role of Serpin and Cystatin Antiproteases in Mucosal Innate Immunity and their Defense against <scp>HIV</scp>

Aboud, Lindsay G.; Ball, T. Blake; Tjernlund, Annelie; Burgener, Adam

doi:10.1111/aji.12166

Cited by 31 publications

(31 citation statements)

References 74 publications

(96 reference statements)

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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: 91%

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: 91%

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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“…5). Factors overabundant during the follicular phase were associated with biofunctions that underlie cellular adherence and epithelial barrier integrity, as well as inflammation mediation (39)(40)(41). This may help in maintaining an environment less likely to contribute to HIV infection since various studies have highlighted the role of inflammatory conditions such as STIs and some forms of bacterial vaginosis in increasing susceptibility to HIV infection (42,43).…”

Section: Discussionmentioning

confidence: 99%

“…Protease inhibitors were found at higher levels during the follicular phase and are known regulators of inflammation. Higher levels of these antiproteases may help to reduce inflammatory processes, while at the same time perform innate antiviral functions (39), which may in turn help prevent the establishment of an HIV founder population if a woman is infected during this time. In fact, higher levels of antiproteases have been associated with HIV resistance in highly exposed seronegative female sex workers (23,44).…”

Section: Discussionmentioning

confidence: 99%

“…For example, cornifin B, cornulin, desmoglein 3,and cystatins are components of the epithelium that are important for generating and maintaining a cohesive keratinocyte barrier that is both flexible and yet impermeable (33)(34)(35)(36). Although serine protease inhibitors (serpins) aid in wound healing, epithelial damage repair, and the inhibition of inflammatory proteases, all of these functions contribute to a healthy, adherent, defensive barrier (37)(38)(39).…”

Section: Participant Characteristicsmentioning

confidence: 99%

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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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“…15 In general, these protease inhibitors function as anti-inflammatory factors by inhibiting the proteases secreted by immune cells, such as neutrophils, which can trigger the activation of the complement system and secretion of other inflammatory mediators that can lead to tissue damage and severe inflammation. 16 Protease inhibitors are expressed throughout the entire FRT, including in the vagina, cervix, uterus and even the fetal membranes. Cervical and vaginal epithelial cells have been shown to express most of these protease inhibitors.…”

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confidence: 99%

Innate and adaptive immune responses in male and female reproductive tracts in homeostasis and following HIV infection

et al. 2014

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The male and female reproductive tracts are complex microenvironments that have diverse functional demands. The immune system in the reproductive tract has the demanding task of providing a protective environment for a fetal allograft while simultaneously conferring protection against potential pathogens. As such, it has evolved a unique set of adaptations, primarily under the influence of sex hormones, which make it distinct from other mucosal sites. Here, we discuss the various components of the immune system that are present in both the male and female reproductive tracts, including innate soluble factors and cells and humoral and cell-mediated adaptive immunity under homeostatic conditions. We review the evidence showing unique phenotypic and functional characteristics of immune cells and responses in the male and female reproductive tracts that exhibit compartmentalization from systemic immunity and discuss how these features are influenced by sex hormones. We also examine the interactions among the reproductive tract, sex hormones and immune responses following HIV-1 infection. An improved understanding of the unique characteristics of the male and female reproductive tracts will provide insights into improving clinical treatments of the immunological causes of infertility and the design of prophylactic interventions for the prevention of sexually transmitted infections.

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The Role of Serpin and Cystatin Antiproteases in Mucosal Innate Immunity and their Defense against HIV

Cited by 31 publications

References 74 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

Innate and adaptive immune responses in male and female reproductive tracts in homeostasis and following HIV infection

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