HIV Infection in the Female Genital Tract: Discrete Influence of the Local Mucosal Microenvironment

Center For Gene Therapeutics, Michael G. DeGroote Institute of Infectious Diseases Research, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
American Journal Of Reproductive Immunology (Impact Factor: 2.44). 04/2010; 63(6):566-75. DOI: 10.1111/j.1600-0897.2010.00843.x
Source: PubMed


Citation Kaushic C, Ferreira VH, Kafka JK, Nazli A. HIV infection in the female genital tract: discrete influence of the local mucosal microenvironment. Am J Reprod Immunol 2010
Women acquire HIV infections predominantly at the genital mucosa through heterosexual transmission. Therefore, the immune milieu at female genital surfaces is a critical determinant of HIV susceptibility. In this review, we recapitulate the evidence suggesting that several distinctive innate immune mechanisms in the female genital tract (FGT) serve to significantly deter or facilitate HIV-1 infection. Epithelial cells lining the FGT play a key role in forming a primary barrier to HIV entry. These cells express Toll-like receptors and other receptors that recognize and respond directly to pathogens, including HIV-1. In addition, innate biological factors produced by epithelial and other cells in the FGT have anti-HIV activity. Female sex hormones, co-infection with other pathogens and components in semen may also exacerbate or down-modulate HIV transmission. A combination of innate and adaptive immune factors and their interactions with the local microenvironment determine the outcome of HIV transmission. Improving our understanding of the female genital microenvironment will be useful in developing treatments that augment and sustain protective immune responses in the genital mucosa, such as microbicides and vaccines, and will provide greater insight into viral pathogenesis in the FGT.

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Available from: Aisha Nazli, Jan 19, 2015
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    • "A central issue in women’s health in developing countries is choice of contraceptive with minimal effects on susceptibility to infectious diseases, in particular to human immunodeficiency virus (HIV)-1 acquisition via the female reproductive tract (FRT). Epithelial cells lining the FRT are the first line of defence against pathogens and serve not only as a physical barrier but also express a wide variety of immune mediators aiding in both innate and adaptive immunity [1]–[3]. Interleukin (IL)-6, IL-8 and regulated-upon-activation-normal-T-cell-expressed-and-secreted (RANTES) are expressed in both primary and immortalised vaginal and cervical epithelial cells [4]–[6]. "
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    ABSTRACT: Clinical studies suggest that the injectable contraceptive medroxyprogesterone acetate (MPA) increases susceptibility to infections such as HIV-1, unlike the injectable contraceptive norethisterone enanthate (NET-EN). We investigated the differential effects, molecular mechanism of action and steroid receptor involvement in gene expression by MPA as compared to NET and progesterone (P4) in the End1/E6E7 cell line model for the endocervical epithelium, a key point of entry for pathogens in the female genital mucosa. MPA, unlike NET-acetate (NET-A) and P4, increases mRNA expression of the anti-inflammatory GILZ and IκBα genes. Similarly, MPA unlike NET-A, decreases mRNA expression of the pro-inflammatory IL-6, IL-8 and RANTES genes, and IL-6 and IL-8 protein levels. The predominant steroid receptor expressed in the End1/E6E7 and primary endocervical epithelial cells is the glucocorticoid receptor (GR), and GR knockdown experiments show that the anti-inflammatory effects of MPA are mediated by the GR. Chromatin-immunoprecipitation results suggest that MPA, unlike NET-A and P4, represses pro-inflammatory cytokine gene expression in cervical epithelial cells via a mechanism involving recruitment of the GR to cytokine gene promoters, like the GR agonist dexamethasone. This is at least in part consistent with direct effects on transcription, without a requirement for new protein synthesis. Dose response analysis shows that MPA has a potency of ∼24 nM for transactivation of the anti-inflammatory GILZ gene and ∼4-20 nM for repression of the pro-inflammatory genes, suggesting that these effects are likely to be relevant at injectable contraceptive doses of MPA. These findings suggest that in the context of the genital mucosa, these GR-mediated glucocorticoid-like effects of MPA in cervical epithelial cells are likely to play a critical role in discriminating between the effects on inflammation caused by different progestins and P4 and hence susceptibility to genital infections, given the predominant expression of the GR in primary endocervical epithelial cells.
    Full-text · Article · May 2014 · PLoS ONE
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    • "STIs may contribute to breaches in the vaginal epithelium allowing HIV to cross this barrier more easily. STIs also may contribute to an increase in activated immune cells (such as CD4+ target cells) within the epithelium, making infection easier.33 In some cases, mucosal shedding associated with some STIs may generate this influx of activated CD4+ cells for months after healing, facilitating the transmission of HIV even after STI treatment.34 "
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    ABSTRACT: Women and adolescent girls bear a significant burden of the global HIV pandemic. Both behavioral and biomedical prevention approaches have been shown to be effective. In order to foster the most effective combination HIV-prevention approaches for women and girls, it is imperative to understand the unique biological, social, and structural considerations that increase vulnerability to acquiring HIV within this population. The purpose of this article is to propose novel ideas for personalized biobehavioral HIV prevention for women and adolescent girls. The central argument is that we must transcend unilevel solutions for HIV prevention toward comprehensive, multilevel combination HIV prevention packages to actualize personalized biobehavioral HIV prevention. Our hope is to foster transnational dialogue among researchers, practitioners, educators, and policy makers toward the actualization of the proposed recommendations. We present a commentary organized to review biological, social, and structural factors that increase vulnerability to HIV acquisition among women and adolescent girls. The overview is followed by recommendations to curb HIV rates in the target population in a sustainable manner. The physiology of the lower female reproductive system biologically increases HIV risk among women and girls. Social (eg, intimate partner violence) and structural (eg, gender inequality) factors exacerbate this risk by increasing the likelihood of viral exposure. Our recommendations for personalized biobehavioral HIV prevention are to (1) create innovative mechanisms for personalized HIV risk-reduction assessments; (2) develop mathematical models of local epidemics; (3) prepare personalized, evidence-based combination HIV risk-reduction packages; (4) structure gender equity into society; and (5) eliminate violence (both physical and structural) against women and girls. Generalized programs and interventions may not have universal, transnational, and crosscultural implications. Personalized biobehavioral strategies are needed to comprehensively address vulnerabilities at biological, social, and structural levels.
    Full-text · Article · Sep 2013
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    • "Genital epithelial cells (ECs) are primary sentinels in the female genital tract (FGT) [1], [2]. ECs express a number of pattern-recognition receptors (PRRs) involved in viral recognition, including Toll-like receptors (TLRs) 2, 3, 4, 7, 8 and 9 and RNA helicases, retinoic acid inducible gene (RIG)-I and melanoma-differentiation-associated gene 5 (MDA5) [3], [4], [5], [6]. Sensing of viruses, including HIV-1, through PRRs initiates a series of signal transduction events that activate key transcription factors, including nuclear factor-kappa B (NF-κB) [7], [8], that induce innate [9], [10], [11], [12] and adaptive [13], [14] immune responses. "
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    ABSTRACT: Elafin (E) and its precursor trappin-2 (Tr) are alarm antiproteases with antimicrobial and immunomodulatory activities. Tr and E (Tr/E) have been associated with HIV-1 resistance. We recently showed that Tr/E reduced IL-8 secretion and NF-κB activation in response to a mimic of viral dsRNA and contributed to anti-HIV activity of cervicovaginal lavage fluid (CVL) of HIV-resistant (HIV-R) commercial sex workers (CSWs). Additionally, Tr, and more so E, were found to inhibit attachment/entry and transcytosis of HIV-1 in human endometrial HEC-1A cells, acting through virus or cells. Given their immunomodulatory activity, we hypothesized that Tr/E could exert anti-HIV-1 activity at multiple levels. Here, using tagged and untagged Tr/E proteins, we comparatively evaluated their protease inhibitory, anti-HIV-1, and immunomodulatory activities, and cellular distribution. E appeared to function as an autocrine/paracrine factor in HEC-1A cells, and anti-HIV-1 activity of E depended on its unmodified N-terminus and altered cellular innate activation, but not its antiprotease activity. Specifically, exogenously added N-terminus-unmodified E was able to enter the nucleus and to reduce viral attachment/entry and transcytosis, preferentially affecting R5-HIV-1(ADA), but not X4-HIV-1(IIIB). Further, anti-HIV-1 activity of E was associated with significantly decreased HIV-1-triggered IL-8 release, attenuated NF-κB/p65 nuclear translocation, and significantly modulated mRNA expression of innate sensors TLR3 and RIG-I in HEC-1A cells. Most importantly, we found that elevated Tr/E in CVLs of HIV-R CSWs were associated with lower mRNA levels of TLRs 2, 3, 4 and RIG-I in the genital ECs from this cohort, suggesting a link between Tr/E, HIV-1 resistance and modulated innate viral recognition in the female genital mucosa. Collectively, our data indicate that unmodified N-terminus is critical for intranuclear localization and anti-HIV-1 activity of E. We also propose that E-mediated altered cellular innate activation most likely contributes to the HIV-R phenotype of these subjects.
    Full-text · Article · Dec 2012 · PLoS ONE
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