Host Genetics of HIV-1 Subtype C Infection, Progression, and Treatment in Africa

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DESCRIPTION (provided by applicant): Previous studies on host susceptibility genes for HIV/AIDS have focused on Caucasian men infected with HIV-1B. This represents a major disconnect with populations at greatest risk, which are women infected with HIV-1C in southern Africa. Little is known about the role of host genetic factors on non-B HIV-1 infection and progression or on HAART response in African populations. Botswana has led the region in the use of HAART. We hypothesize that genetic factors affecting risk of HIV-1 disease may be different i n southern African heterosexuals infected with HIV-1 subtype C and may explain in part the higher prevalence, differences in disease patterns, and the spectrum of adverse events related to HAART. We propose to evaluate the role of host genetic variation in known AIDS restriction genes (ARGs), innate immunity factors (Cul5, KIR, APOBEC3G, APOBEC3F, and TRIMS and related gene family members), complement factors, mitochondria! genes, selected immune response modifiers and HIV-1 co-receptors (cytokines and cytokine receptors, chemokines and chemokine receptors), HLA class 1 genes and host factors required for HIV-1 life cycle on: 1) susceptibility to HIV-1 C infection; 2) trajectories of CD4 T cell and HIV-1 C RNA levels in HIV-infected persons; 3) efficacy of HAART in persons with AIDS; and 4) development of specific AIDS-defining conditions in HAART-treated and untreated persons. Specific Aims: 1. To investigate the influence of functional genotypic variants in selected genes on susceptibility to HIV-1 C. 2. To investigate the influence of functional genotypic variants in selected genes on the trajectory of CD4+ T cell and HIV RNA levels in HIV-1 infected adults before initiating ARV treatment. 3. To investigate the role of functional genotypic variants in selected genes on HAART efficacy and adverse events. 4. To investigate the role of functional genotypic variants on specific AIDS-defining conditions. AIDS resistance gene discovery and characterization in African cohorts is critical from at least four perspectives: /') to implicate host factors that would alter risk for infection and influence pathogenesis; //) to identify new host avenues suitable for therapy development, /'/'/) to define confounders of ART efficacy and adverse events; and iv) to provide co-variates for clinical management of ART patients in Africa.