The development of an effective HIV-1 vaccine has been hampered by the rapid rate of mutation and genetic variation throughout the viral genome, especially the env gene. In this proposal, we seek to analyze the evolution of HIV clade C env genes in children that were perinatally infected. In parallel, we will analyze the evolution of env genes in rhesus monkeys infected with SHIV strains encoding the corresponding HIV clade C env genes. We hypothesize that the molecular evolution of env genes in the two different species will follow similar patterns. Together with Core A, we will generate new SHIV strains that encode env genes from HIV clade C-infected Zambian infants with rapid HIV disease progression. We hypothesize that Env is a determinant for pathogenicity, which will be mirrored in the corresponding SHIV strains in macaques. The overall objective of Project 1 is to determine whether infection of non-human primates by SHIV and the resultant 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 characterize the patterns and within-host diversification of clade C env genes. Using nucleotide sequence data from viral isolates obtained in parallel from infected humans and macaques, we will test several hypotheses regarding the relationships among genetic diversity, disease progression, and clinical phenotypes. This proposal will make use of an ongoing research project to study perinatal transmission of HIV and other viruses in mother/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 in the 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 infected animals, 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 and macaques with time, and correlate these changes to disease progression. This study will provide important predictive information about the evolution of HIV clade C by correlating patterns of env evolution with pathogenesis and disease progression. This study will also lead to a better understanding of the host-virus interaction during the disease course and will provide useful information for designing vaccines.
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