Abstract
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.
Highlights
RNA viruses exist as extremely diverse populations, with every possible spontaneous mutation along the genome appearing within each patient every day [1]
By analyzing the frequency of premature stop codons, we show that the HIV-1 mutation rate in vivo is two orders of magnitude higher than that predicted by in vitro studies, making it the highest reported mutation rate for any biological system
HIV-1 is subject in vivo to editing by cellular enzymes of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (A3) family, which are packaged into the virion and, upon infection of a new cell, mediate the edition of cytidine to uracil in the negative-strand viral cDNA, resulting in G!A substitutions in the viral genomic RNA [13,14,15]
Summary
RNA viruses exist as extremely diverse populations, with every possible spontaneous mutation along the genome appearing within each patient every day [1] This diversity plays a fundamental role in HIV-1 biology, enabling the virus to successfully evade the immune system, rapidly modify cell tropism, evolve drug resistances, and thwart vaccination strategies [2,3]. The HIV-1 reverse transcriptase (RT) lacks proofreading activity and has an estimated error rate on the order of 3 × 10−5 per base per round of copying as determined in cell culture studies [4,6,7,8,9] These estimates may not truly reflect the mutational process of HIV-1 in patients, because cellular factors such as dNTP levels or sequence context can affect the frequency and type of mutations produced [10,11,12]. The HIV-1 mutation rate in vivo, the contribution of the HIV-1 RT, and host A3 proteins to this rate, as well as its relevance to disease progression, remain to be elucidated
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