Fifteen to Twenty Percent of HIV Substitution Mutations Are Associated with Recombination

Abstract

i HIV undergoes high rates of mutation and recombination during reverse transcription, but it is not known whether these events occur independently or are linked mechanistically. Here we used a system of silent marker mutations in HIV and a single round of infection in primary T lymphocytes combined with a high-throughput sequencing and mathematical modeling approach to directly estimate the viral recombination and mutation rates. From >7 million nucleotides (nt) of sequences from HIV infection, we observed 4,801 recombination events and 859 substitution mutations (Ϸ1.51 and 0.12 events per 1,000 nt, respectively). We used experimental controls to account for PCR-induced and transfection-induced recombination and sequencing error. We found that the single-cycle virus-induced mutation rate is 4.6 ؋ 10 ؊5 mutations per nt after correction. By sorting of our data into recombined and nonrecombined sequences, we found a significantly higher mutation rate in recombined regions (P ‫؍‬ 0.003 by Fisher's exact test). We used a permutation approach to eliminate a number of potential confounding factors and confirm that mutation occurs around the site of recombination and is not simply colocated in the genome. By comparing mutation rates in recombined and nonrecombined regions, we found that recombination-associated mutations account for 15 to 20% of all mutations occurring during reverse transcription.

Northern African Strains of Human T-Lymphotropic Virus Type 1 Arose from a Recombination Event

“…enetic recombination is a major characteristic of the human retrovirus HIV-1 and plays a crucial role in evolution and pathogenicity (1,2). In contrast, no recombination event has been described, so far, for human T-lymphotropic virus type 1 (HTLV-1), the first described human-pathogenic retrovirus (3).…”

Models of Viral Population Dynamics

“…HIV replication is a highly erroneous process with an average mutation rate of 1.4-4.6 × 10 −5 per base per generation (Abram et al 2010;Mansky and Temin 1995;Schlub et al 2014) driving the rapid emergence of drug-resistant strains and treatment failure. Describing the development of drug resistance requires explicit consideration of viral subpopulations with different combinations of potential drug resistance mutations.…”

“…HIV recombines at a very high rate, 0.8-1.5 × 10 −3 per site per reverse transcription (Levy et al 2004;Schlub et al 2014;Suryavanshi and Dixit 2007). Infections by heterozygous virions allow recombination to bring together or drive apart mutations, affecting viral diversity.…”

On the importance of skewed offspring distributions and background selection in virus population genetics

“…All of these aspects characterize, for example, HIV, a diploid virus with extraordinary rates of recombination (Schlub et al, 2014). Transmitted and founder viruses undergo at least two distinct genetic bottlenecks (one at physical transmission and one at infection, respectively; Joseph and Swanstrom, 2015), followed by strong selection imposed by the immune system (Moore et al, 2002).…”