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155 HIV-1 Infection and Replication in Cervico-Vaginal Histocultures

Saba1, Elisa2; Lisco, A1; Vanpouille, C1; Grivel, J C1; Poli, G2; Margolis, Leonid1

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2011 - Volume 56 - Issue - p 64
doi: 10.1097/01.qai.0000397340.33353.66

1Program in Physical Biology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA; and 2AIDS Immunopathogenesis Unit, San Raffaele Scientific Institute, Milano, ITALY

The mucosal immune system of the lower female genital tract plays a key role in HIV-1 transmission and pathogenesis. While in other tissues HIV-1 infection of CD4 T cells is known to depend on cellular activation, differentiation and expression of HIV-1 co-receptors for cervico-vaginal tissue (CVT) these key characteristics remain unknown. To address this problem we developed an ex vivo system of cervical explants that efficiently support HIV replication. We investigated by FACS analysis the differentiation and activation state of CD4 T cells extracted from CVT blocks obtained from HIV-1 negative (HIV-1neg) volunteers. CD4 T cells isolated from CVT showed an effector memory phenotype with a peculiar pattern of expression of activation markers. CVT blocks were infected with either R5-HIV-1BaL or X4-HIV-1LAI strains; productive infection of HIV-1 was documented by ELISA for p24Gag, and by RNA quantification by real-time PCR. Also, we identified p24gag expressing cells by FACS analysis. CVT inoculated with R5-HIV-1BaL efficiently supported virus replication, whereas X4-HIV-1LAI replicated only in the few tissues enriched in CD27 + CD28 + CD4 TEM cells. Ex novo HIV replication rather than virus absorption was demonstrated to occur and was abolished by either inhibitors of HIV reverse transcriptase (3TC) or of viral entry (PSC-RANTES). For R5-HIV-1BaL, p24Gagpos cells were mostly activated (CD38+) CD4 T cells although a similar state of activation of p24Gagneg (bystander) CD4 T cells was also observed. We can conclude that CD4 T cells present in CVT of HIV-1neg individuals are in a predominantly activated state and express CCR5. These features are likely responsible for the susceptibility of CVT to support productive infection of R5-HIV-1. In contrast, X4-HIV-1 replication was negligible except in a few tissues implying that co-expression of CD4 and CXCR4 in lymphocytes of CVT is not sufficient to support productive infection of X4 HIV-1.

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