Awarded Project: "Estrogen reverses progestin-mediated increases in susceptibility to genital virus pathogens"

Estrogen reverses progestin-mediated increases in susceptibility to genital virus pathogens

Dr. Christopher J. Miller, in conjunction with Stanford University, received a five year grant from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, NIH. Prior work from our research group revealed that while depot-medroxyprogesterone acetate (DMPA) and other progestins used for contraception compromise genital mucosal barrier function, treatment of humanized mice with DMPA and estrogen (E) restores barrier integrity and blocks genital HIV transmission. These results identify unforeseen advantage of hormonal contraceptive strategies that use progestin and E (i.e., they avoid weakening of genital mucosal barrier protection caused by progestins alone). In this proposal, we will acquire essential information related to this approach by: 1) using mouse models to define E-mediated mechanisms that boost genital mucosal barrier function; 2) confirm mouse data in rhesus macaques (RM) administered DMPA and an E-releasing intravaginal ring (E-IVR); and 3) show genital SIV transmission is blocked in RM administered DMPA and E-IVR prior to infection.

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R01 DH094634 Abstract:

HIV affects more women than any other life-threatening infectious agent. It is most often sexually transmitted, where virus must evade the genital mucosal barrier to cause systemic infection. Clinical studies suggest HIV more easily overcomes this defense in women using the injectable progestin depot-medroxyprogesterone acetate (DMPA). Offering biological plausibility for this possibility, we previously showed that DMPA promotes mouse susceptibility to HSV-2 infection by reducing expression of the cell-cell adhesion molecule desmoglein-1 (DSG1) and increasing genital mucosal permeability. DMPA similarly enhances susceptibility of humanized mice to genital infection with cell-associated HIV-1. Corroborating these findings in clinical investigation, we showed that women initiating DMPA demonstrate changes in ectocervical DSG1 expression and mucosal permeability identical to those seen in mice. Moreover, pharmacologically relevant DMPA doses in rhesus macaques (RM) comparably enhance genital mucosal permeability to low molecular weight molecules. On the other hand, we re-utilized a humanized mouse model of HIV infection to uncover that combined treatment with DMPA and intravaginal (ivag) E prevents DMPA-mediated loss of genital mucosal barrier function and blocks genital transmission of the virus. These results thus potentially identify an unexpected advantage of hormonal contraceptive strategies that combine use of exogenous progestin and E (i.e., they avert the loss of genital mucosal barrier function induced by progestin use alone). As necessary steps in exploring this approach, this proposal will elucidate mechanisms of E-mediated enhancement of genital mucosal barrier function and define capacity of an E-releasing ivag ring (E-IVR) to protect RM from genital SIV transmission. In Aim 1, we will perform studies in mice to define E-mediated regulation of genital mucosal integrity and barrier function. We will also formulate a RM-sized E-IVR to deliver pharmacologically relevant drug doses and use these rings to compare DSG1 expression and genital mucosal barrier function in RM treated with DMPA, DMPA and placebo IVR, or DMPA and E-IVR (Aim 2). In Aim 3, we will compare genital SIV transmission in RM administered DMPA, DMPA and placebo IVR, or DMPA and E-IVR with repetitive genital challenges with escalating virus inoculums. Completion of this work will identify molecular mechanisms by which E promotes genital epithelial integrity and newly establish that exogenous E blocks SIV transmission in RM by abrogating DMPA-mediated weakening of genital mucosal barrier function. This proposal will thus deliver important new information in two highly relevant clinical models and support further exploration of comparable strategies in populations at high risk for acquiring HIV.

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Awarded Project: "Estrogen reverses progestin-mediated increases in susceptibility to genital virus pathogens"

Estrogen reverses progestin-mediated increases in susceptibility to genital virus pathogens

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Awarded Project: "Estrogen reverses progestin-mediated increases in susceptibility to genital virus pathogens"

Estrogen reverses progestin-mediated increases in susceptibility to genital virus pathogens

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Christopher J. Miller, DVM, PhD