The overall aim of the project is to elucidate the host and viral factors that influence the set point in heterosexually acquired HIV subtype C infection. A high risk cohort of 100 sex workers participating in a HIV prevention study and a cohort of 400 high risk women, who are not sex workers, participating in a prevention microbicide trial in Durban will be followed-up monthly using RNA-PCR to identify 30-35 acute seroconvertors each year. After viral detection, samples will be collected weekly for the first month for comprehensive evaluation of immunological and viral factors involved in the initial control of viral replication. Following this, samples will be collected fortnightly until 3 months post infection, monthly until set point is reached and thereafter quarterly for the duration of the study. Viral loads will be assessed sequentially over time, to determine the magnitude of and time taken to reach the set point. The impact of viral diversity and viral evolution, following acquisition and during the early stages of infection, on the viral set point will be investigated. Escape from immune recognition in early infection, and rates of evolution in different regions of the genome in different stages of the disease will be assessed. The frequency of HIV-1 variants with mutations and polymorphisms associated with drug resistance will be assessed over time in anticipation of the increasing utilization of antiretroviral therapy. The frequency, stability and the level of resistance conferred by different mutations will be assessed and correlated with the viral set point. The breadth and magnitude of CTL, T helper and neutralizing antibody responses will be monitored closely during the acute stage of infection and correlated with viral set point. The impact of CTL and neutralizing antibody pressure on subtype C viral genome diversity will be assessed and correlated with the rates of viral evolution, viral escape and potential loss of viral control. Other host factors being investigated include early clinical events, severity of the acute retroviral disease, intercurrent illnesses, HLA alleles/haplotypes and co-receptor polymorphisms. Since the set point is currently the best available predictor of progression of HIV infection to clinical disease and death, it is an important primary outcome of trials of HIV therapy and prevention. Hence an elucidation of factors that influence the set point will have direct relevance to understanding host and viral parameters that are relevant for future HIV prevention and therapeutic research.
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