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Open Access Highly Accessed Research

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

Hongshuo Song1, Jeffrey W Pavlicek1, Fangping Cai1, Tanmoy Bhattacharya113, Hui Li4, Shilpa S Iyer4, Katharine J Bar4, Julie M Decker6, Nilu Goonetilleke7, Michael KP Liu7, Anna Berg1, Bhavna Hora1, Mark S Drinker1, Josh Eudailey1, Joy Pickeral9, M Anthony Moody18, Guido Ferrari9, Andrew McMichael7, Alan S Perelson3, George M Shaw45, Beatrice H Hahn45, Barton F Haynes1102 and Feng Gao12*

Author Affiliations

1 Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA

2 Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA

3 Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM, 87545, USA

4 Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

5 Department of Microbiology, University of Pennsylvania, Philadelphia, PA, 19104, USA

6 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

7 Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, England, OX3 9DS, UK

8 Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA

9 Department of Surgery, Duke University Medical Center, Durham, NC, 27710, USA

10 Department of Immunology, Duke University Medical Center, Durham, NC, 27710, USA

11 The Santa Fe Institute, Santa Fe, NM, 87501, USA

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Retrovirology 2012, 9:89  doi:10.1186/1742-4690-9-89

Published: 30 October 2012

Abstract

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.

Keywords:
Human immunodeficiency virus type I; Viral fitness; Cytotoxic T lymphocytes; Immune escape mutation; Transmitted/founder virus; Mathematical model