Extremely High Mutation Rate of HIV-1 In Vivo

Rates of spontaneous mutation critically determine the genetic diversity and evolution of RNA viruses. Although these rates have been characterized in vitro and in cell culture models, they have seldom been determined in vivo for human viruses. Here, we use the intrapatient frequency of premature st...

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Bibliographic Details
Published in:PLoS biology 2015-09, Vol.13 (9), p.e1002251-e1002251
Main Authors: Cuevas, José M, Geller, Ron, Garijo, Raquel, López-Aldeguer, José, Sanjuán, Rafael
Format: Article
Language:English
Subjects:
Acquired immune deficiency syndrome
Adult
AIDS
Disease Progression
Female
Genes
HIV
HIV Infections - virology
HIV-1 - genetics
Human immunodeficiency virus
Humans
Male
Middle Aged
Mutation
Mutation Rate
Sequence Analysis, RNA
Young Adult
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Summary:Rates of spontaneous mutation critically determine the genetic diversity and evolution of RNA viruses. Although these rates have been characterized in vitro and in cell culture models, they have seldom been determined in vivo for human viruses. Here, we use the intrapatient frequency of premature stop codons to quantify the HIV-1 genome-wide rate of spontaneous mutation in DNA sequences from peripheral blood mononuclear cells. This reveals an extremely high mutation rate of (4.1 ± 1.7) × 10-3 per base per cell, the highest reported for any biological entity. Sequencing of plasma-derived sequences yielded a mutation frequency 44 times lower, indicating that a large fraction of viral genomes are lethally mutated and fail to reach plasma. We show that the HIV-1 reverse transcriptase contributes only 2% of mutations, whereas 98% result from editing by host cytidine deaminases of the A3 family. Hypermutated viral sequences are less abundant in patients showing rapid disease progression compared to normal progressors, highlighting the antiviral role of A3 proteins. However, the amount of A3-mediated editing varies broadly, and we find that low-edited sequences are more abundant among rapid progressors, suggesting that suboptimal A3 activity might enhance HIV-1 genetic diversity and pathogenesis.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.1002251