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: Introduction: HIV affects more women than any other life‐threatening infectious agent, and most infections are sexually transmitted. HIV must breach the female genital tract mucosal barrier to establish systemic infection, and clinical studies indicate virus more easily evades this barrier in women using depot‐medroxyprogesterone acetate (DMPA) and other injectable progestins for contraception. Identifying a potential mechanism for this association, we learned DMPA promotes susceptibility of wild‐type mice to genital herpes simplex virus type 2 (HSV‐2) infection by reducing genital tissue expression of the cell‐cell adhesion molecule desmoglein‐1 (DSG‐1) and increasing genital mucosal permeability. Conversely, DMPA‐mediated increases in genital mucosal permeability and HSV‐2 susceptibility were eliminated in mice concomitantly administered exogenous oestrogen (E). To confirm and extend these findings, herein we used humanized mice to define effects of systemic DMPA and intravaginal (ivag) E administration on susceptibility to genital infection with cell‐associated HIV‐1. Methods: Effects of DMPA or an intravaginal (ivag) E cream on engraftment of NOD‐scid‐IL‐2Rgc[sup.null] (NSG) mice with human peripheral blood mononuclear cells (hPBMCs) were defined with flow cytometry. Confocal microscopy was used to evaluate effects of DMPA, DMPA and E cream, or DMPA and the pharmacologically active component of the cream on vaginal tissue DSG‐1 expression and genital mucosal permeability to low molecular weight (LMW) molecules and hPBMCs. In other studies, hPBMC‐engrafted NSG mice (hPBMC‐NSG) received DMPA or DMPA and ivag E cream before genital inoculation with 10[sup.6] HIV‐1‐infected hPBMCs. Mice were euthanized 10 days after infection, and plasma HIV‐1 load quantified by qRT‐PCR and splenocytes used to detect HIV‐1 p24 antigen via immunohistochemistry and infectious virus via TZM‐bl luciferase assay. Results: Whereas hPBMC engraftment was unaffected by DMPA or E treatment, mice administered DMPA and E (cream or the pharmacologically active cream component) displayed greater vaginal tissue expression of DSG‐1 protein and decreased vaginal mucosal permeability to LMW molecules and hPBMCs versus DMPA‐treated mice. DMPA‐treated hPBMC‐NSG mice were also uniformly susceptible to genital transmission of cell‐associated HIV‐1, while no animal concomitantly administered DMPA and E cream acquired systemic HIV‐1 infection. Conclusion: Exogenous E administration reduces susceptibility of DMPA‐treated humanized mice to genital HIV‐1 infection., Introduction Women aged 15 to 24 years in sub‐Saharan Africa are especially vulnerable to HIV, and currently represent 25% of the new infections in the region. Reasons for this are [...]

PU20.01 Vaccination with Ad26.ZEBOV, MVA-BN-Filo or MVA-BN-Filo, Ad26.ZEBOV induced predominantly IgG binding to Ebola glycoprotein in cervico-vaginal mucus in HIV-infected and uninfected participants S. Akapirat (1) ; J. Puangkaew (1) [...]

Background: Injectable progestin-only contraceptives (IPCs), including Depo-Provera (DMPA), have been associated with HIV acquisition risk in some epidemiological studies and in animal models. This risk has not been consistently observed and the risk of IPCs must be weighed against the known benefits of effective contraception. Regardless, understanding how IPCs shape the mucosal environment of the female genital tract can help elucidate biological mechanisms underlying their potential impact on HIV acquisition risk and may lead to new HIV prevention strategies. Methods: Cervical cytobrushes were collected from HIV-uninfected women aged 18 to 23 years through the FRESH (Females Rising through Education, Support, and Health) study in Umlazi, South Africa, and cervical epithelial and CD4+ T cells were FACS-sorted. RNAseq was performed on the sorted cells and data was analyzed using STAR, HTSeq, DESeq2, and GSEA. Results: Cervical epithelial cells were compared between women who reported using DMPA (n = 6) and women in the follicular phase of the menstrual cycle by reported last menstrual period (n = 6). tSNE clustering showed clear segregation between groups, and 369 genes were significantly differentially expressed. Of these genes, two of the most highly expressed in DMPA users were CCL3 and CCL3L3, mediators of T cell homing. GSEA analysis demonstrated that the epithelial gene sets most significantly over-expressed in DMPA-using women were keratinization, cellular response to IFNg, and keratinocyte differentiation (FDR q < 0.05). Parallel analysis of cervical CD4+ T cells identified 5 significantly differentially expressed genes (fold change >90) and a significantly enriched gene set in DMPA users, 'positive regulation of T cell mediated immunity' (FDR q-val 0.087). Conclusions: In DMPA users, cervical epithelial cells express higher levels of the T cell homing cytokines CCL3 and CCL3L3, while cervical CD4+ T cells exhibit inflammatory gene set enrichment. At the same time, keratinization pathways may be altered in DMPA users, as suggested in previous literature. Together, these results suggest possible mechanisms by which progestins may contribute to genital inflammation and/or differential barrier function in the genital mucosa. These findings may point towards potential biological approaches to reduce HIV acquisition risk in women., OA19.03 E.H. Byrne (1); M. Farcasanu (2); S. Bloom (3); N. Xulu (4); J. Xu (2); S. Handley (5); J. Bramante (2); C. Mitchell (6); A.-C. Villani (7) and D.S. [...]