Extremely High Mutation Rate of HIV-1 In Vivo

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.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…This concept also applies to HIV drugs such as efavirenz with a half-life of 58 h, and stavidune and lamivudine with half-lives of 5-12 h. If the viral burden is 10²⁰ virions in the body with a mutation rate of 4 × 10 − ³ to 2 × 10 − ⁵ per base per cell and a doubling time of 10 h, the virus would be exposed to efivarenz monotherapy for a period of 2 weeks (ie, >30 doubling times). 174 In the standard antituberculosis regimen, rifampicin and isoniazid both have a short half-life of 2-3 h and pyrazinamide has a half-life of 10 h, while M tuberculosis has a doubling time of 14-96 h and the mutation rates (2·56 × 10 − ⁸ for isoniazid, 2·56 × 10 − ⁷ for ethambutol, and 2·25 × 10 − ¹⁰ for rifampin) identified by David, 167 with a The Lancet Respiratory Medicine Commission total bacterial burden of 10⁸ in a cavity. [175][176][177][178] The antibiotics are no longer present because clearance occurs before a single M tuberculosis has replicated, and certainly by the second and third replications.…”

Probabilistic recovery of cryptic haplotypes from metagenomic data

“…This is in contrast to pol, where the closest matching haplotypes to the original HIV strains were in the top 6 most likely reconstructions. This likely represents differing numbers of novel cryptic haplotypes of these genes and correlates well with their known mutation rates in vivo [28].…”

“…This is in contrast to pol, where the closest matching haplotypes to the original HIV strains were in the top 6 most likely reconstructions. This likely represents differing numbers of novel cryptic haplotypes of these genes and correlates well with their known mutation rates in vivo [28].For all of the recovered HIV-1 haplotypes, Figure 4 plots the scaled BLAST bitscores against the Gretel likelihood score. Each recovered haplotype is matched to its closest strain.…”

Six wedges to curing disease

“…An example is limited drug diffusion through tumors leading to spatial refuges and resistance [4,18]. Fifth, agents may naturally have high mutation rates, or be induced or selected to have increased mutation rates, such as in hypermutator bacteria [19], HIV [20], and certain cancers [21]. Tumors in particular are thought to contain numerous resistant variants by the time neoplasms are typically discovered [22].…”