Mucosal susceptibility to human immunodeficiency virus infection in the proliferative and secretory phases of the menstrual cycle

Factors underlying HIV acquisition in women remain incompletely understood. This study evaluated ex vivo mucosal HIV-1_BaL infection (ectocervix, endocervix), T cell frequencies and phenotype (ectocervix, endocervix, peripheral blood), and HIV-1_BaL-induced tissue immune responses (ectocervix) in the proliferative and secretory phases of the menstrual cycle using samples obtained from women undergoing hysterectomies. Tissue infectivity (number of productively infected explants) and infection level following 500 and/or fifty 50% tissue culture infectious dose (TCID_50) HIV-1_BaL challenge were similar in the proliferative and secretory phases. Although not associated with infection outcomes, higher frequencies of HIV target CD4+α4β7+ T cells, and stronger HIV-1_BaL-induced proinflammatory responses were detected in ectocervix in the secretory versus proliferative phase. Independently of the cycle phase, serum E2 concentrations were inversely associated with ectocervical and endocervical tissue infection levels following high-dose 500 TCID_50 HIV-1_BaL challenge, with frequencies of CD4+α4β7+ T cells in endocervix, and with HIV-induced interleukin (IL)2R and IL4 in ectocervix. Although serum P4 concentrations and P4/E2 ratios were neither associated with tissue infection level nor infectivity, high P4 concentrations and/or P4/E2 ratios correlated with high frequencies of CD4+α4β7+ T cells in ectocervix, low frequencies of CD4+CD103+ blood T cells, low CD4+LFA-1+ T cells in endocervix, and high proinflammatory (IL1β, IL17, tumor necrosis factor α) ectocervical tissue responses to HIV-1_BaL. The data suggest an inhibitory effect of E2 on mucosal HIV infection, provide insights into potential mechanisms of E2-mediated anti-HIV activity, and highlight P4-associated immune changes in the mucosa

Comparative transcriptome analysis of the human endocervix and ectocervix during the proliferative and secretory phases of the menstrual cycle

Despite extensive studies suggesting increased susceptibility to HIV during the secretory phase of the menstrual cycle, the molecular mechanisms involved remain unclear. Our goal was to analyze transcriptomes of the endocervix and ectocervix during the proliferative and secretory phases using RNA sequencing to explore potential molecular signatures of susceptibility to HIV. We identified 202 differentially expressed genes (DEGs) between the proliferative and secretory phases of the cycle in the endocervix (adjusted p \u3c 0.05). The biofunctions and pathways analysis of DEGs revealed that cellular assembly and epithelial barrier function in the proliferative phase and inflammatory response/cellular movement in the secretory phase were among the top biofunctions and pathways. The gene set enrichment analysis of ranked DEGs (score = log fold change/p value) in the endocervix and ectocervix revealed that (i) unstimulated/not activated immune cells gene sets positively correlated with the proliferative phase and negatively correlated with the secretory phase in both tissues, (ii) IFNγ and IFNα response gene sets positively correlated with the proliferative phase in the ectocervix, (iii) HIV restrictive Wnt/β-catenin signaling pathway negatively correlated with the secretory phase in the endocervix. Our data show menstrual cycle phase-associated changes in both endocervix and ectocervix, which may modulate susceptibility to HIV