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: 3.32). 04/2010; 63(6):566-75. DOI: 10.1111/j.1600-0897.2010.00843.x
Source: PubMed

ABSTRACT 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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    ABSTRACT: 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.Cellular & Molecular Immunology advance online publication, 30 June 2014; doi:10.1038/cmi.2014.41.
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    ABSTRACT: Background Sexual transmission is the main route of HIV-1 infection and the CCR5-using (R5) HIV-1 is predominantly transmitted, even though CXCR4-using (X4) HIV-1 is often abundant in chronic HIV-1 patients. The mechanisms underlying this tropism selection are unclear. Mucosal Langerhans cells (LCs) are the first immune cells to encounter HIV-1 and here we investigated the role of LCs in selection of R5 HIV-1 using an ex vivo epidermal and vaginal transmission models. Results Immature LCs were productively infected by X4 as well as R5 HIV-1. However, only R5 but not X4 viruses were selectively transmitted by immature LCs to T cells. Transmission of HIV-1 was depended on de novo production of HIV-1 in LCs, since it could be inhibited by CCR5 fusion inhibitors as well as reverse transcription inhibitors. Notably, the activation state of LCs affected the restriction in X4 HIV-1 transmission; immune activation by TNF facilitated transmission of X4 as well as R5 HIV-1. Conclusions These data suggest that LCs play a crucial role in R5 selection and that immature LCs effectively restrict X4 at the level of transmission.
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