Proinflammatory Oscillations Over the Menstrual Cycle Drives Bystander CD4 T Cell Recruitment and SHIV Susceptibility from Vaginal Challenge

Background: The menstrual cycle influences HIV infection-risk in women, although the timing and underlying mechanism are unclear. Here we investigated the contribution of the menstrual cycle to HIV susceptibility through evaluating immune behavior with infection-risk over time. Methods: Pigtail macaques were used to evaluate immune changes over reproductive cycles and in a low-dose repetitive vaginal virus challenge model. PBMC samples from healthy women were collected over the course of a cycle and measured for T cell characteristics. Immune properties from PBMC and vaginal lavage samples were measured by flow cytometry. Progesterone concentration from blood plasma was measured by enzyme immunoassay. The oscillation frequency of progesterone concentration and CCR5 expression from CD4 T cells was calculated using the Lomb-Scargle periodogram. SHIV infection was detected from blood plasma by Q-PCR.       Findings: From macaques, cycle-phases associated with fluctuations in systemic immune properties which identified a type-1 inflammatory response bias with corresponding CCR5+ CD4 T cell (HIV target cell) infiltration into the vaginal lumen at the late luteal phase. Power spectral analysis detected CCR5 oscillation frequencies synchronized with reproductive cycles, and in a repetitive low-dose vaginal challenge model, productive SHIV163P3 infection occurred from inoculation during those intervals of mounting type-1 responses. Finally, we observe similar sinusoidal inflammatory properties in healthy menstruating women.  Interpretation: These data demonstrate that periodic shifts in the immune landscape under menstrual cycle regulation drive bystander CCR5+ CD4 T cell recruitment, corresponding to the tissue remodeling functions at the late luteal phase, and increases HIV susceptibility in the female reproductive tract. Funding Statement: This study was supported by the U.S. Centers for Disease Control and Prevention, Atlanta, GA 30329 and NIH grants to Emory University (K23AI114407to A.N.S., the Emory University Center for AIDS research [P30AI050409], and Atlanta Clinical and Translational Sciences Institute [KLR2TR000455, UL1TR000454]). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All [animal] procedures were approved by the Institutional CDC Animal Care and Use Committee (IACUC). Protocols were approved by the Emory University Institutional Review Board, the U.S. Centers for Disease Control and Prevention Institutional Review Board, and the Grady Research Oversight Committee.