While the viral set point has been extensively studied in subtype B infections, there is little data on subtype C infection. The set point in the southern African context may differ from the situation elsewhere due to quality of the immune response, HLA alleles, co-receptor polymorphisms, inter-current infections, or possibly unique feature of subtype C viruses.

HIV viral load, CD4+, T cell count and CD8+ T cell responses have been proposed as surrogate endpoints in clinical trials to assess HIV vaccines, which are hypothesized to prevent or delay the onset of AIDS. The purpose of this study is to examine the pathogenesis of acute HIV-1 subtype C infection and characterize these potential vaccine endpoints. Specifically it investigates the relationship between the magnitude and breadth of CD8+ T cell responses in early infection, viral load at 12 months post infection, and disease progression in HIV-1 subtype C infected individuals. In this study, a single viral load measurement at 12 months post infection is used as a surrogate marker of viral set point with viral load measurements at 6 and 18 months also analyzed to determine which best predicts disease progression. The relationship between cellular and humoral immune responses, viral genetic changes and viral loads in acute, early and established infection will be characterized and the impact of immune pressure and viral escape on viral load trajectory will be determined. The study also seeks to define clinical features of acute HIV infection, i.e. acute retroviral syndrome.

Participants with acute HIV infection will be identified from:

• a cohort of female sex workers in KwaZulu-Natal;
• participants in a Phase II/IIb microbicide trial (HPTN035) in Durban; and,
• research cohorts in Vulindlela (females and males) and

Viral loads will be assessed prospectively, 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 will be assessed over time. 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 coreceptor polymorphisms.

This project proposes to provide essential information on the viral set point that informs both the design and analysis of future therapeutic and vaccine efficacy trials in southern Africa.