title: Minimal Contribution of APOBEC3-Induced G-to-A Hypermutation to HIV-1 Recombination and Genetic Variation.
abstract: Although the predominant effect of host restriction APOBEC3 proteins on HIV-1 infection is to block viral replication, they might inadvertently increase retroviral genetic variation by inducing G-to-A hypermutation. Numerous studies have disagreed on the contribution of hypermutation to viral genetic diversity and evolution. Confounding factors contributing to the debate include the extent of lethal (stop codon) and sublethal hypermutation induced by different APOBEC3 proteins, the inability to distinguish between G-to-A mutations induced by APOBEC3 proteins and error-prone viral replication, the potential impact of hypermutation on the frequency of retroviral recombination, and the extent to which viral recombination occurs in vivo, which can reassort mutations in hypermutated genomes. Here, we determined the effects of hypermutation on the HIV-1 recombination rate and its contribution to genetic variation through recombination to generate progeny genomes containing portions of hypermutated genomes without lethal mutations. We found that hypermutation did not significantly affect the rate of recombination, and recombination between hypermutated and wild-type genomes only increased the viral mutation rate by 3.9 × 10-5 mutations/bp/replication cycle in heterozygous virions, which is similar to the HIV-1 mutation rate. Since copackaging of hypermutated and wild-type genomes occurs very rarely in vivo, recombination between hypermutated and wild-type genomes does not significantly contribute to the genetic variation of replicating HIV-1. We also analyzed previously reported hypermutated sequences from infected patients and determined that the frequency of sublethal mutagenesis for A3G and A3F is negligible (4 × 10-21 and1 × 10-11, respectively) and its contribution to viral mutations is far below mutations generated during error-prone reverse transcription. Taken together, we conclude that the contribution of APOBEC3-induced hypermutation to HIV-1 genetic variation is substantially lower than that from mutations during error-prone replication.
authors.affiliation: Viral Mutation Section, HIV Dynamics and Replication Program, National Cancer Institute at Frederick, Frederick, Maryland, United States of America.
authors.forename: Krista A
authors.identifier: 0000-0003-3370-8542
authors.initials: KA
authors.lastname: Delviks-Frankenberry
authors.affiliation: Viral Recombination Section, HIV Dynamics and Replication Program, National Cancer Institute at Frederick, Frederick, Maryland, United States of America.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Nikolaitchik
authors.affiliation: Viral Mutation Section, HIV Dynamics and Replication Program, National Cancer Institute at Frederick, Frederick, Maryland, United States of America.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Burdick
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Lab, Frederick, Maryland, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gorelick
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Lab, Frederick, Maryland, United States of America.
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.affiliation: Viral Recombination Section, HIV Dynamics and Replication Program, National Cancer Institute at Frederick, Frederick, Maryland, United States of America.
authors.forename: Wei-Shau
authors.initials: WS
authors.lastname: Hu
authors.affiliation: Viral Mutation Section, HIV Dynamics and Replication Program, National Cancer Institute at Frederick, Frederick, Maryland, United States of America.
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Pathak
mesh_terms: D000071478:APOBEC Deaminases; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000378:metabolism*; D014644:Genetic Variation / Q000235:genetics*; D057809:HEK293 Cells; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D009154:Mutation; D059645:Mutation Rate; D016133:Polymerase Chain Reaction; D011995:Recombination, Genetic / Q000235:genetics*
chemical_list: D043525:Cytosine Deaminase; D000071478:APOBEC Deaminases; C502889:APOBEC3 proteins, human; D003564:Cytidine Deaminase