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Search for the mechanism of genetic variation in the pro gene of human immunodeficiency virus.

TitleSearch for the mechanism of genetic variation in the pro gene of human immunodeficiency virus.
Publication TypeJournal Article
Year of Publication1999
AuthorsIM Rouzine, Coffin, JM
JournalJ Virol
Volume73
Issue10
Pagination8167-78
Date Published1999 Oct
ISSN0022-538X
KeywordsBase Sequence, Evolution, Molecular, Genes, Viral, Genetic Variation, HIV Protease, HIV-1, Humans, Models, Genetic, Molecular Sequence Data
Abstract

To study the mechanism of evolution of the human immunodeficiency virus (HIV) protease gene (pro), we analyzed a database of 213 pro sequences isolated from 11 HIV type 1-infected patients who had not been treated with protease inhibitors. Variation in pro is restricted to rare variable bases which are highly diverse and differ in location among individuals; an average variable base appears in about 16% of individuals. The average intrapatient distance per individual variable site, 27%, is similar for synonymous and nonsynonymous sites, although synonymous sites are twice as abundant. The latter observation excludes selection for diversity as an important, permanently acting factor in the evolution of pro and leaves purifying selection as the only kind of selection. Based on this, we developed a model of evolution, both within individuals and along the transmission chain, which explains variable sites as slightly deleterious mutants slowly reverting to the better-fit variant during individual infection. In the case of a single-source transmission, genetic bottlenecks at the moment of transmission effectively suppress selection, allowing mutants to accumulate along the transmission chain to high levels. However, even very rare coinfections from independent sources are, as we show, able to counteract the bottleneck effect. Therefore, there are two possible explanations for the high mutant frequency. First, the frequency of coinfection in the natural host population may be quite low. Alternatively, a strong variation of the best-adapted sequence between individuals could be caused by a combination of an immune response present in early infection and coselection.

Alternate JournalJ. Virol.
PubMed ID10482567
PubMed Central IDPMC112834
Grant ListR35 CA044385 / CA / NCI NIH HHS / United States
R35 CA44385 / CA / NCI NIH HHS / United States