The overall goal of the UAB AIEDRN application is to provide three established patient cohorts, key personnel and resources, scientific leadership, and hypothesis-driven research proposals for pursuing the stated aims of the AIEDRN: Elucidation of HIV-1 pathogenesis in acute and early infection and development and evaluation of therapeutic intervention. As members of this network, we will provide three patient cohorts (Alabama, Florida, Zambia); expertise in epidemiology, experimental therapeutics, viral pathogenesis, immunology, and immunogenetics; and research proposals which focus on the molecular composition of virus reservoirs in vivo, and the impact of antiretroviral therapy, host immunogenetic profile, and early immunologic response on virus containment. Specifically, we propose to evaluate the following hypotheses: (i) Plasma virus load, and its prognostically important """"""""set-point,"""""""" provide a quantitative assessment of overall virus replication in tissue sites relevant to disease pathogenesis. (ii) A comprehensive assessment of virus load (RNA and DNA), expression (RNA), replication capacity (defective, latent, productive), genotype, phenotype, and targets of infection in blood and lymphoreticular tissues, before and after initiation of therapy, provides additional insight into the dynamics of virus replication not attainable by analysis of plasma viral RNA alone; such studies will elucidate the frequency and lifespan of infected cell reservoirs, reveal the genetic pathways to multidrug resistance, and provide important virologic """"""""benchmarks"""""""" for developing rational treatment strategies for virus eradication or long-term suppression. (iii) The kinetic profile of plasma virus decline in early infection and its observed """"""""set-point"""""""" are substantially influenced by both viral and host factors, including host immune response and immunogenetics.
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