HIV-1 sexual transmission: early events of HIV-1 infection of human cervico-vaginal tissue in an optimized ex vivo model

Abstract

Infection and dissemination of HIV-1 through the female body after vaginal intercourse depends on the activation/differentiation status of mucosal CD4 T cells. Here, we investigated this status and the susceptibility to HIV-1 infection of human cervico-vaginal tissue ex vivo. We found that virtually all T cells are of the effector memory phenotype with broad CCR5 expression. As it does in vivo, human cervico-vaginal tissue ex vivo preferentially supports the productive infection of R5 HIV-1 rather than that of X4 HIV-1 in spite of broad expression of CXCR4. X4 HIV-1 replicated only in the few tissues that were enriched in CD27+CD28+ effector memory CD4 T cells. Productive infection of R5 HIV-1 occurred preferentially in activated CD38+CD4 T cells and was followed by a similar activation of HIV-1-uninfected (bystander) CD4 T cells that may amplify viral infection. These results provide new insights into the dependence of HIV-1 infection and dissemination on the activation/differentiation of cervico-vaginal lymphocytes.

Human Immunodeficiency Virus Infects Human Seminal Vesicles in Vitro and in Vivo

“…Such prototypic non-primary R5 and X4 strains have been widely used to test the susceptibility to HIV infection of a range of tissues including the cervix, prostate gland, foreskin, and penis. 26,[31][32][33][34][35] With use of these two strains, we demonstrated that the human seminal vesicles are selectively infected by macrophage-tropic HIV-1 R5 ex vivo and release infectious virions. The R5 SF162 strain consistently replicated in the seminal vesicle tissues, as assessed by increased reverse transcriptase activity in seminal vesicle supernatants during culture, increased level of viral DNA in the explants, PBMC infection by the viral particles recovered from the infected seminal vesicle supernatants, and in situ detection of infected cells in the explants using immunohistochemistry for HIV p24.…”

ART influences HIV persistence in the female reproductive tract and cervicovaginal secretions

“…Hence, both intraepithelial Langerhans cells and DCs have potential important roles in vaginal HIV transmission (65)(66)(67)(68)(69). However, the mucosa of the human FRT contains an abundance of CD4 + T cells (24,25,34,68), and experiments in both NHPs (nonhuman primates) and human explant models suggest that the first productively infected cells are likely T cells (61, 68, 70-73). (21).…”

“…To confirm that cells in the FRT of BLT mice have a similar memory phenotype as in women (24,33,34), we characterized the naive-memory phenotype of T cell subsets in PB, the FRT, and CVS (naive: CD45RA in humans and BLT mice results in a dramatic decrease in the levels of CD4 + T cells in the FRT and CVS that is not reflected in PB. In previous studies, no determination was made about whether the observed decrease in CD4 + T cells in the FRT was due to a reduction in the number of CD4 + T cells and/or an increase in the number of CD8 + T cells (33,49,50).…”

Aging impacts CD103+CD8+ T cell presence and induction by dendritic cells in the genital tract

“…In the FRT, more than 95% of T cells are effector memory (Saba et al., 2010; Yeaman et al., 1997), with a high proportion of T cells expressing CD103 in the vagina, endocervix (CX), ectocervix (ECX), and endometrium (EM) (Duluc et al., 2013; Moylan et al., 2016; Rodriguez‐Garcia et al., 2017). Along with resident T cells, mucosal surfaces are populated by multiple subsets of resident DCs critical for the induction and maintenance of T‐cell responses (Schlitzer, McGovern & Ginhoux, 2015).…”