Sources and implications of HIV-1 diversity within women in Mombasa, Kenya

The human immunodeficiency virus type 1 (HIV-1) has a remarkable capacity to diversify within infected individuals. In this thesis, sources of HIV-1 diversity---evolution, superinfection, and hypermutation---are examined among HIV-infected Kenyan women in a longitudinal cohort study. The potential role of these processes in disease progression and implications for HIV-1 treatment and prevention are discussed.;This thesis first describes relationships between HIV-1 evolution in two genes, markers of disease progression, and immune parameters. Our results show that there is higher diversity and divergence in env than gag, however, evolution in these genes is strongly correlated. Gag divergence and mutations in gag CTL epitopes are associated with higher viral load, while env divergence and neutralizing antibody breadth are not. Therefore, there are gene-specific differences in evolution that may reflect different immune pressures and have different effects on disease progression.;This thesis next describes the incidence and timing of HIV-1 superinfection among women in this cohort. Six superinfection cases were identified by screening gag sequences from a total of 50 women, and another 6 cases have been found by screening env sequences. Thus, the incidence of superinfection in this group is 4.7% per year, which may not be substantially different from the rate of initial infection. Moreover, superinfection occurred throughout infection and by closely related viruses, suggesting that there was no protection conferred by the immune response to the first infection in these individuals.;Finally, this thesis examines APOBEC3G-induced hypermutation, which may impair virus replication by introducing deleterious mutations. However, greater hypermutation is not associated with lower viral load or higher CD4 count in this group. One individual, who had extensive hypermutation and a partially defective Vif, sustained a relatively high viral load. Together, these results suggest that a moderate amount of hypermutation is not sufficient to impair HIV-1 replication.;These studies demonstrate the complexity of within-host HIV-1 populations, as well as the wealth of information that is available in a large, longitudinal study. Increasing our understanding of HIV-1 diversity and its impact on pathogenesis and transmission will be essential in considering new strategies for HIV prevention and treatment.