HIV/AIDS has spread relentlessly since it was first identified in 1983, causing one of the most devastating pandemics in human history. Historical accounts of infectious diseases show that they can have a major impact on U.S. Armed Forces. With 34 million individuals infected worldwide, HIV-1 poses a significant and persistent threat to force readiness and the stability of many nation-states. The incidence of HIV/AIDS infection among U.S. service personnel is significant and the risk of exposure to HIV-1 by heterosexual intercourse among veterans and service personnel is much greater. Heterosexual HIV-1 transmission from men to women accounts for the majority of new infections worldwide, and notably, women are entering into military service at an increasing rate. The discovery of effective prevention modalities for women is hindered by a lack of basic information about early virus-host interactions in the female genital tract mucosa that underlie the acquisition of HIV-1 infection. Non-human primate (NHP) models of HIV/SIV transmission indicate that macrophages and predominantly CD4 T cells become infected within the first few days after high-dose intravaginal challenge. The observation of early CD4 T cell infection seemed consistent with subsequent published work indicating transmitted/founder (TF) viruses generally exhibit low to moderate tropism for monocyte-derived macrophages (MDM). However, recent published and unpublished data (Preliminary Studies) would argue that this central question regarding HIV-1 transmission biology, and the role of macrophages in particular, warrants additional investigation. Our central hypothesis is that cervical macrophages are required to drive HIV-1 replication and spread in the cervical mucosa. Our corollary hypothesis, though beyond the immediate scope of this application, is that cervical macrophages (cM?s) are required for expansion and spread of HIV-1 infection beyond initial foci of infected CD4 T cell in the mucosa, and thus represent an underlying determinant of mucosal HIV-1 heterosexual transmission in women. To interrogate this central hypothesis, we propose the following specific aims: (1) To characterize the dynamics of HIV-1 infection and replication in human cervical explant tissue; (2) To determine the spatiotemporal relationships between uninfected and HIV-1 infected cM?s and CD4 T lymphocytes in cervical tissue in situ; and (3) To identify cellular determinants of cM?s susceptibility to HIV-1 infection. Our research promise to elucidate critical virus-host interactions that underlie the establishment of HIV-1 infection in the female mucosal genital tract. Validation of our central hypothesis would impart a paradigm shift in the field, and implicate cM?s as a viable early target for the discovery of new HIV/AIDS prevention strategies.
? RELEVANCE FOR PUBLIC HEALTH This research application addresses a fundamental gap in our understanding of mucosal HIV-1 transmission: How is HIV-1 infection established in the female genital tract mucosa? Fundamental questions remain unanswered regarding the significance of mucosal macrophages as early targets of HIV-1 infection, mechanisms and pathways by which cervical macrophages become infected, their role in early virus amplification and spread, and virologic and cellular determinants that affect their susceptibility to HIV-1 infection. The research proposed in this grant application will elucidate the role of tissue macrophages in establishing HIV-1 infection of cervical explant tissue, and thereby will inform the development of interventions modalities aimed at preventing mucosal HIV-1 transmission.
