GSE100094
Fluctuations in sex hormones affect ex vivo HIV infection in cervical mucosa and mucosal immunity
There is an ongoing debate whether sex hormones impact risk of HIV transmission. This study evaluated if serum estradiol (E2) and progesterone (P4) levels predict the ex vivo cervical tissue HIV infection, tissue immune environment and transcriptome. Cervical mucosa and peripheral blood samples were collected from subjects undergoing total hysterectomies. Tissue explants were challenged with HIV-1BaL and infection was monitored in the supernatants by HIV gag qRT-PCR. Serum E2 and P4 concentrations were measured by radioimmunoassay. Blood and tissue T cell phenotypes were characterized by flow cytometry. Tissue responses to HIV exposure were measured by Luminex. Tissue transcriptome in an unchallenged portion of mucosa was analyzed by RNAseq. We show that serum E2 concentrations inversely associated with cervical HIV-1BaL infection ex vivo and this association was independent of potential confounders (race, age, phase of the cycle, parakeratosis, metaplasia, histopathological signs of cervical inflammation, and HSV-2 status). E2 concentrations did not associate with T cell frequencies/phenotype in either tissues or blood. However, higher E2 concentrations predicted a mixed profile of pro-/anti-inflammatory genes expression and HIV-induced soluble mediators. In contrast, P4 concentrations or P4/E2 ratios did not associate with ex vivo tissue infection level, but increased P4 concentrations associated with high frequencies of a4b7+ and low LFA-1+ T cells and mainly pro-inflammatory responses to HIV. These data suggest inhibitory effect of E2 on local mucosal HIV amplification early post transmission, provide insights in the mechanism of E2-mediated anti-HIV activity and highlight P4-associated immune changes in the mucosa. Overall design: Endocervical samples were derived from subjects with high (n=5; 205-599 pg/ml) vs. low-moderate (n=5; 27-109 pg/ml) estradiol concentrations. Ectocervical samples were derived from subjects with high (n=3; 277-599pg/ml) vs. low-moderate (n=4; 27-109 pg/ml) E2 levels.