10th Conference on Retroviruses and Opportunistic Infections Boston, MA USA - February 10 -14, 2003

Conf Retroviruses Opportunistic Infect 2003 Feb 10-14;10th: abstract no. 4
J Coffin
Director, HIV Drug Resistance Program, NCI-FCRDC, Frederick, MD, and American Cancer Society Research Professor, Tufts University, Boston, MA

BACKGROUND: Retroviruses are unique among infectious agents in their ability to provide insight into their own evolution, the evolution of their host, and the evolution of the host-virus relationship. I will discuss two different aspects of retrovirus-host evolution.

METHODS: First, because of their unique replication cycle requiring integration of the DNA provirus into host cell DNA, retrovirus genetic information has become fixed as endogenous proviruses in the germline, where they persist and provide an abundant “fossil record” of long-extinct viruses. Current estimates are that the human genome contains some 80,000 proviruses (or fragments), substantially outnumbering genes. We have been studying one group of these proviruses, called HERV-K, which shows evidence of having been active in widely separated waves, between least 30 million and about 5 million years ago. We have used the special properties of the long terminal repeats (LTRs) that flank proviruses as sensitive indicators of the evolutionary processes that have shaped the genome, such as recombination leading to large-scale chromosome shuffling, inversion, and deletion. We found that these events have occurred during human evolution, and have been fixed about once every 80,000 years. A sensitive blotting technique informed by the genome database, gives evidence for relatively recent activity of these elements, including integration at new sites, and formation of solo LTRs by internal recombination. Whether such activity continues today, and its importance in human disease remain open questions. HIV infection also presents unique evolutionary issues, the most important of which is the nearly inevitable appearance of drug-resistant virus, the most important factor preventing successful therapy. Modeling suggests that resistance mutations arise prior to initiation of therapy, and that their frequency is critically dependent on factors such as the population size, mutation rate, selection effects, and recombination. To understand these effects better, we have initiated a study in which the genetic variation in HIV in patients is intensively monitored.

CONCLUSIONS: Our results to date imply a large population of replicating virus, which becomes very diverse with time, but is subject to significant purifying selective forces that serve to stabilize the diversity. Implications of these results for the evolution of drug-resistant virus will be discussed.

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