Treatment of HIV-1 infection with combinations of highly active antiretroviral agents (HAART) has achieved remarkable suppression of viral replication in many individuals whereas others have rapidly become resistant to treatment. Compared to adults, children generally develop higher as well as more sustained HIV-1 loads early in infection, which may predispose them to rapid development of disease and drug resistance. Understanding viral evolution in children during HAART will aid in tailoring treatment regimens for optimal efficacy. Hence, the Principal Investigator proposed to (1) define the kinetics of viral and T cell turnover in HIV1-infected children and, specifically, determine if the high viral loads found in children are the result of increased viral production or impaired clearance; (2) determine the rate of viral evolution in children before and after HAART, through an analysis of viral env and pro, as well as markers of antiviral resistance in pol; (3) define the mode of viral recombination, a process that would allow the combination of important genetic traits with minimal cycles of viral replication compared to that required for the progressive selection for additive mutations in the development of HIV-1 resistance to HAART as the continued evolution of provirus in children with plasma HIV-1 RNA levels below the level of detection would indicate the persistence of partially suppressed replication competent virus, whereas the lack of evolution would be consistent with complete suppression of viral replication] understanding the mechanisms of the development of viral resistance is critical to optimizing HIV-1 treatment strategies; and (4) to improve understanding of the driving forces of viral evolution in vivo, and because differences in tissue penetration and intracellular metabolism of antivirals may allow the evolution of resistant viruses within certain cell types, to determine whether resistance to HAART is associated with changes in virus cell tropism and co-receptor use.
