HIV-1 evolution: Role of diversity and fitness---implications for the epidemic

Human Immunodeficiency virus is a rapidly evolving virus, constantly mutating to escape host immune recognition. A stronger diversifying pressure by the immune system on the env gene is thought to be responsible for this high mutation rate, while other genes like the gag and pol that are under less diversifying pressure and more purifying selection pressure show lower rates. Not only is there an increase in viral quasispecies as the disease progresses but there is also coreceptor evolution from the CCR5- (R5) using viral variants that predominate in the early and asymptomatic phase of infection to the CXCR4 (X4) (and the dual-tropic R5X4) variants that are normally found in the late stage of the disease. Furthermore, as the disease progresses, HIV evolves from the less fit to the more fit variants such that in end-stage disease, there is a diverse viral population that is predominantly CXCR4-using and exhibiting increased fitness. Using selective inhibition of each phenotype by either drugs or U87.CD4 cells that express either of the receptors, we found that in dual-tropic isolates, the CXCR4 phenotype is the major determinant of viral fitness.;HIV-1 subtype C is dominating the global epidemic and is rapidly spreading both as a pure subtype and as a recombinant. The reasons for this rapid spread are not yet well delineated. Using two well characterized cohorts; a subtype A and D cohort and a subtype C cohort, we found that the rates of CD4 cell declines were much slower in the subtype C. The slower CD4 cells declines coupled with the reduced fitness of this subtype plus efficient transmission as well as the fact that subtype C rarely switches from CCR5 to CXCR4, may be part of the reason this subtype is dominating in the epidemic.