Recombination is a fundamental property of genetic material, which allows patterns of evolutionary change that would be virtually impossible without it. Although normally associated with sexual reproduction, recombination may also play a critical role in allowing non-sexually reproducing organisms to adapt to a changing environment. In the case of HIV-1, the recombigenic potential of this retrovirus has been noted in settings in which individuals were dually infected with two divergent viral variants. However, the high mutation rate of this virus, along with its rapid replication to high level and long persistence within the infected host, permit enough diversity to develop to allow the detection, by recently developed techniques, of recombination events within individuals infected with monophyletic viruses. The potential impact of such recombination on disease course, especially in the face of multi-drug therapy which can only be resisted through the acquisition of numerous mutations, is the focus of the proposed studies.
The specific aims are to 1) Sequence regions of the env and pol gene from 24 individuals infected by a single source of HIV-1 and followed longitudinally in order to monitor intrahost evolution. 2) Simultaneously estimate the evolutionary trees and recombinational history from the sequence data using newly developed analytical procedures. 3) Use the longitudinal data available on each individual to examine the evolutionary fate of recombinant versus non-recombinant haplotypes in order to test for interactions between recombination, selection, and adaptive evolution of HIV-1. The analysis will separate the effects of intragenic versus intergenic recombination. 4) Test for associations between the evolutionary patterns observed for recombinants and the course of disease progression and treatment regimes. These studies should provide critical insights into the potential rate of emergence of multi-drug resistant variants of HIV-1.
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