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Memory CD4+ T Cells Are the Earliest Detectable Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Cells in the Female Genital Mucosal Tissue during HIV-1 Transmission in an Organ Culture System

Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA. pgupta1+@pitt.edu
Journal of Virology (Impact Factor: 4.65). 11/2002; 76(19):9868-76. DOI: 10.1128/JVI.76.19.9868-9876.2002
Source: PubMed

ABSTRACT The virologic and cellular factors that are involved in transmission of human immunodeficiency virus type 1 (HIV-1) across the female genital tissue are poorly understood. We have recently developed a human cervical tissue-derived organ culture model to study heterosexual transmission of HIV-1 that mimics the in vivo situation. Using this model we investigated the role of phenotypic characteristics of HIV-1 and identified the cell types that are first infected during transmission. Our data indicate that the cell-free R5 HIV-1 was more efficiently transmitted than cell-free X4 HIV-1. Cell-free and cell-associated HIV-1 had comparable transmission efficiency regardless of whether the virus was of R5 or X4 type. We have demonstrated that memory CD4(+) T cells and not Langerhans cells were the first HIV-1 RNA-positive cells detected at the epithelial-submucosal junction 6 h after virus exposure. Multicolor laser confocal microscopy demonstrated a globular distribution of HIV-1 gag-pol mRNA in the cytoplasm, and the distribution of CD4 and the CD45RO isoform was irregular on the cellular membrane. At 96 h postinoculation, in addition to memory CD4(+) T cells, HIV-1 RNA-positive Langerhans cells and macrophages were also detected. The identification of CD4(+) T cells in the tissue at 6 h was confirmed by flow cytometric simultaneous immunophenotyping and ultrasensitive fluorescence in situ hybridization assay on immune cells isolated from disaggregated tissue. Furthermore, PMPA [9-[2-(phosphonomethoxy)propyl] adenine], an antiretroviral compound, and UC781, a microbicide, inhibited HIV-1 transmission across the mucosa, indicating the utility of the organ culture to screen topical microbicides for their ability to block sexual transmission of HIV-1.

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    • "These cells are also present in the lamina propria, subepithelial stroma, and the epithelium (Edwards and Morris, 1985; Hickey et al., 2011; Johansson et al., 1999). Findings using human vaginal explants show that CD4 þ T cells are relevant to HIV-1 transmission because HIV-1 productively infects both activated and resting CD4 þ T cells in the genital mucosa (Gupta et al., 2002; Hladik et al., 2007; Zhang et al., 1999). Whether DCs, Langerhans cells, and monocytes present in the cervicovaginal Fig. 5. Human semen-derived exosomes decrease murine susceptibility to LP-BM5 mAIDS virus infection: (A) schematic representation of experimental procedure. "
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    Virology 08/2015; 482. DOI:10.1016/j.virol.2015.03.040 · 3.28 Impact Factor
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    • "Infection by both cell-free and cell-associated virus has been observed in female macaques infected with simian immunodeficiency and chimeric viruses (SIV/SHIV) (Gupta et al., 2002; Kaizu et al., 2006; Khanna et al., 2002; Salle et al., 2010; Zhu et al., 1996), mice infected with HIV (Khanna et al., 2002), and indirectly in humans through genetic matching of HIV viruses sequenced from acutely infected women and from seminal cells and plasma from their infected partners (Zhu et al., 1996). Human cervical explant studies have also confirmed transmission of cell-free and cell-associated HIV (Gupta et al., 2002). Both forms of HIV are carried by semen and deposited in the vagina during intercourse. "
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    • "Exposure of the cervical explants to a topical formulation of UC-781 resulted in blocking of subsequent HIV-1 viral infection of mucosal tissue and transinfection mediated by migratory cells without toxicity, indicating that UC-781 may be a good candidate microbicide. PMPA {9-[2-(phosphonomethoxy)propyl]adenine}, a nucleotide analogue that blocks viral replication by inhibiting reverse transcriptase , was also shown to be able to inhibit viral transmission across the mucosa (Gupta et al., 2002). These findings support the utility of organ cultures with human mucosal tissues to screen topical microbicides for their ability to block sexual transmission of HIV-1. "
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