HIV-1 Infection in the Female Reproductive Tract: Role of Interactions between HIV-1 and Genital Epithelial Cells

Department of Pathology and Molecular Medicine, Michael DeGroote Center for Learning and Discovery, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada.
American Journal Of Reproductive Immunology (Impact Factor: 2.44). 03/2011; 65(3):253-60. DOI: 10.1111/j.1600-0897.2010.00965.x
Source: PubMed


Citation Kaushic C. HIV-1 infection in the female reproductive tract: role of interactions between HIV-1 and genital epithelial cells. Am J Reprod Immunol 2011; 65: 253–260
Despite recent progress in understanding the mucosal transmission of human immunodeficiency virus (HIV)-1, the immediate events following transmission in the female genital tract are incompletely understood. Recent in vivo studies in primate models indicate that HIV-1 transmission may occur in the upper or lower genital tract and the initial HIV-1 replication occurs primarily in the target T cells and in some subsets of DCs localized in the genital tract. However, the principal mechanism(s) that allow the virus to cross the primary barrier of genital epithelial cells (GECs) are still unclear. A number of pathways have been proposed as possible ways that HIV-1 could use to cross the epithelium. However, little attention has been paid to the response of GECs to HIV-1. We recently demonstrated that exposure to HIV-1 rapidly upregulates a wide array of pro-inflammatory cytokine production by GECs. Among these cytokines, tumour necrosis factor (TNF)-α impaired the tight junction barrier allowing HIV-1 and luminal bacteria to translocate across the epithelium. This study illustrated that GECs are dynamically active cells that mount rapid host responses to HIV-1, independent of viral replication. Cytokine responses of GECs could play a critical role in HIV transmission and replication. Further understanding of GEC responses to HIV-1 and their regulation could be critical to understanding HIV-1 transmission dynamics during heterosexual transmission.

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Available from: Charu Kaushic, Aug 26, 2015
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    • "Several reports suggest that endogenous steroid hormone levels and synthetic progestins used in contraception, influence susceptibility and disease predisposition to many genital tract infections (reviewed in [2], [11]). Treatment of animals and humans with P4 or synthetic progestins has been reported to increase susceptibility to viral and bacterial infections [12]–[16]. "
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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.
    PLoS ONE 05/2014; 9(5):e96497. DOI:10.1371/journal.pone.0096497 · 3.23 Impact Factor
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    • "Although the mechanism of this transmission has not been examined for HTLV, mucosal entry of HIV and SIV in the genital tracts have been well characterized by in vitro studies of purified cell populations, ex vivo studies using human explants, and in vivo studies in macaques and humanized mice (reviewed in Hladik and McElrath, 2008; Ganor and Bomsel, 2011; Kaushic, 2011). These studies have shown that HIV can be transmitted across the epithelium by all of the methods described above: infected seminal cells, or virus produced by those cells, have been shown to cross through gaps in the epithelium, by infecting the epithelium, or by transcytosis. "
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    ABSTRACT: The deltaretroviruses human T cell lymphotropic virus type 1 (HTLV-1) and human T cell lymphotropic virus type 2 (HTLV-2) have long been believed to differ from retroviruses in other genera by their mode of transmission. While other retroviruses were thought to primarily spread by producing cell-free particles that diffuse through extracellular fluids prior to binding to and infecting target cells, HTLV-1 and HTLV-2 were believed to transmit the virus solely by cell-cell interactions. This difference in transmission was believed to reflect the fact that, relative to other retroviruses, the cell-free virions produced by HTLV-infected cells are very poorly infectious. Since HTLV-1 and HTLV-2 are primarily found in T cells in the peripheral blood, spread of these viruses was believed to occur between infected and uninfected, T cells, although little was known about the cellular and viral proteins involved in this interaction. Recent studies have revealed that the method of transmission of HTLV is not unique: other retroviruses including human immunodeficiency virus (HIV) are also transmitted from cell-to-cell, and this method is dramatically more efficient than cell-free transmission. Moreover, cell-cell transmission of HTLV-1, as well as HIV, can occur following interactions between dendritic cells and T cells, as well as between T cells. Conversely, other studies have shown that cell-free HTLV-1 is not as poorly infectious as previously thought, since it is capable of infecting certain cell types. Here we summarize the recent insights about the mechanisms of cell-cell transmission of HTLV-1 and other retroviruses. We also review in vitro and in vivo studies of infection and discuss how these finding may relate to the spread of HTLV-1 between individuals.
    Frontiers in Microbiology 10/2012; 3:378. DOI:10.3389/fmicb.2012.00378 · 3.99 Impact Factor
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    • "In human astrocytes, HIV binds to hMR and activates MMPs, which in turn degrade the extracellular matrix proteins [20]. In case of primary genital epithelial cells, HIV has also been reported to decrease the expression of tight junction proteins and increase the leakiness of the epithelial layer towards HIV [21], [22]. This led us to hypothesize that hMR may exist on vaginal epithelial cells, which might bind to HIV gp120 leading to production of MMPs, facilitating the degradation of junctional proteins and/or the extracellular matrix in general, thereby inducing a disruption of the epithelial layer organization. "
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    ABSTRACT: During sexual transmission of HIV in women, the virus breaches the multi-layered CD4 negative stratified squamous epithelial barrier of the vagina, to infect the sub-epithelial CD4 positive immune cells. However the mechanisms by which HIV gains entry into the sub-epithelial zone is hitherto unknown. We have previously reported human mannose receptor (hMR) as a CD4 independent receptor playing a role in HIV transmission on human spermatozoa. The current study was undertaken to investigate the expression of hMR in vaginal epithelial cells, its HIV gp120 binding potential, affinity constants and the induction of matrix metalloproteinases (MMPs) downstream of HIV gp120 binding to hMR. Human vaginal epithelial cells and the immortalized vaginal epithelial cell line Vk2/E6E7 were used in this study. hMR mRNA and protein were expressed in vaginal epithelial cells and cell line, with a molecular weight of 155 kDa. HIV gp120 bound to vaginal proteins with high affinity, (Kd = 1.2±0.2 nM for vaginal cells, 1.4±0.2 nM for cell line) and the hMR antagonist mannan dose dependently inhibited this binding. Both HIV gp120 binding and hMR exhibited identical patterns of localization in the epithelial cells by immunofluorescence. HIV gp120 bound to immunopurified hMR and affinity constants were 2.9±0.4 nM and 3.2±0.6 nM for vaginal cells and Vk2/E6E7 cell line respectively. HIV gp120 induced an increase in MMP-9 mRNA expression and activity by zymography, which could be inhibited by an anti-hMR antibody. hMR expressed by vaginal epithelial cells has high affinity for HIV gp120 and this binding induces production of MMPs. We propose that the induction of MMPs in response to HIV gp120 may lead to degradation of tight junction proteins and the extracellular matrix proteins in the vaginal epithelium and basement membrane, leading to weakening of the epithelial barrier; thereby facilitating transport of HIV across the vaginal epithelium.
    PLoS ONE 11/2011; 6(11):e28014. DOI:10.1371/journal.pone.0028014 · 3.23 Impact Factor
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