Impact of immune escape mutations on HIV-1 fitness in the context of the cognate transmitted/founder genome.

Published online

Journal Article

BACKGROUND: A modest change in HIV-1 fitness can have a significant impact on viral quasispecies evolution and viral pathogenesis, transmission and disease progression. To determine the impact of immune escape mutations selected by cytotoxic T lymphocytes (CTL) on viral fitness in the context of the cognate transmitted/founder (T/F) genome, we developed a new competitive fitness assay using molecular clones of T/F genomes lacking exogenous genetic markers and a highly sensitive and precise parallel allele-specific sequencing (PASS) method. RESULTS: The T/F and mutant viruses were competed in CD4+ T-cell enriched cultures, relative proportions of viruses were assayed after repeated cell-free passage, and fitness costs were estimated by mathematical modeling. Naturally occurring HLA B57-restricted mutations involving the TW10 epitope in Gag and two epitopes in Tat/Rev and Env were assessed independently and together. Compensatory mutations which restored viral replication fitness were also assessed. A principal TW10 escape mutation, T242N, led to a 42% reduction in replication fitness but V247I and G248A mutations in the same epitope restored fitness to wild-type levels. No fitness difference was observed between the T/F and a naturally selected variant carrying the early CTL escape mutation (R355K) in Env and a reversion mutation in the Tat/Rev overlapping region. CONCLUSIONS: These findings reveal a broad spectrum of fitness costs to CTL escape mutations in T/F viral genomes, similar to recent findings reported for neutralizing antibody escape mutations, and highlight the extraordinary plasticity and adaptive potential of the HIV-1 genome. Analysis of T/F genomes and their evolved progeny is a powerful approach for assessing the impact of composite mutational events on viral fitness.

Full Text

Duke Authors

Cited Authors

  • Song, H; Pavlicek, JW; Cai, F; Bhattacharya, T; Li, H; Iyer, SS; Bar, KJ; Decker, JM; Goonetilleke, N; Liu, MKP; Berg, A; Hora, B; Drinker, MS; Eudailey, J; Pickeral, J; Moody, MA; Ferrari, G; McMichael, A; Perelson, AS; Shaw, GM; Hahn, BH; Haynes, BF; Gao, F

Published Date

  • October 30, 2012

Published In

Volume / Issue

  • 9 /

Start / End Page

  • 89 -

PubMed ID

  • 23110705

Electronic International Standard Serial Number (EISSN)

  • 1742-4690

Digital Object Identifier (DOI)

  • 10.1186/1742-4690-9-89

Language

  • eng

Conference Location

  • England