The development of an effective HIV-1 vaccine has been hampered by the rapid rate of mutation and geneticvariation throughout the viral genome, especially the env gene. In this proposal, we seek to analyze theevolution of HIV clade C env genes in children that were perinatally infected. In parallel, we will analyze theevolution of env genes in rhesus monkeys infected with SHIV strains encoding the corresponding HIV cladeC env genes. We hypothesize that the molecular evolution of env genes in the two different species willfollow similar patterns. Together with Core A, we will generate new SHIV strains that encode env genesfrom HIV clade C-infected Zambian infants with rapid HIV disease progression. We hypothesize that Env isa determinant for pathogenicity, which will be mirrored in the corresponding SHIV strains in macaques. Theoverall objective of Project 1 is to determine whether infection of non-human primates by SHIV and theresultant molecular evolution of env therein, is a suitable model for studying HIV-1 evolution in humans.Our immediate goal is to longitudinally isolate samples from perinatally infected infants and to characterizethe patterns and within-host diversification of clade C env genes. Using nucleotide sequence data from viralisolates obtained in parallel from infected humans and macaques, we will test several hypotheses regardingthe relationships among genetic diversity, disease progression, and clinical phenotypes. This proposal willmake use of an ongoing research project to study perinatal transmission of HIV and other viruses inmother/infant pairs (MIPs) from Zambia.
The Specific Aims are:1) To characterize changes in Env proteins of HIV-1 clade C isolated from infants at different time points inthe disease course, and correlate these changes to disease progression.2) To characterize Env proteins of SHIV clade C isolated longitudinally over the disease course in infectedanimals, and correlate these changes to disease progression in both the animals and the patients.3) To characterize the biological properties of Env proteins of viruses obtained from the paired patients andmacaques with time, and correlate these changes to disease progression.This study will provide important predictive information about the evolution of HIV clade C by correlatingpatterns of env evolution with pathogenesis and disease progression. This study will also lead to a betterunderstanding of the host-virus interaction during the disease course and will provide useful information fordesigning vaccines.
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