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

• Published in: Retrovirology 2012-10, Vol.9 (1), p.89-89, Article 89
• Main Authors: Song, Hongshuo, Pavlicek, Jeffrey W, Cai, Fangping, Bhattacharya, Tanmoy, Li, Hui, Iyer, Shilpa S, Bar, Katharine J, Decker, Julie M, Goonetilleke, Nilu, Liu, Michael K P, Berg, Anna, Hora, Bhavna, Drinker, Mark S, Eudailey, Josh, Pickeral, Joy, Moody, M Anthony, Ferrari, Guido, McMichael, Andrew, Perelson, Alan S, Shaw, George M, Hahn, Beatrice H, Haynes, Barton F, Gao, Feng
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Analysis; Antigenic determinants; Base Sequence; BASIC BIOLOGICAL SCIENCES; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; Cells, Cultured; Cloning; Colleges & universities; Competition; Cytotoxic T lymphocytes; Cytotoxicity; Development and progression; Disease transmission; Epitopes, T-Lymphocyte - genetics; Epitopes, T-Lymphocyte - immunology; Founder Effect; gag Gene Products, Human Immunodeficiency Virus - genetics; Gene mutations; Genetic aspects; Genetic Fitness; Genetic markers; Genetic research; Genome, Viral; Genomes; Genomics; HIV; HIV (Viruses); HIV-1 - genetics; HIV-1 - immunology; HIV-1 - physiology; HLA-B Antigens - genetics; HLA-B Antigens - immunology; Hospitals; Human immunodeficiency virus; Human immunodeficiency virus 1; Human immunodeficiency virus type I; Humans; Immune escape mutation; Immune Evasion - genetics; Lymphocytes; Mathematical model; Mathematical models; Medicine; Molecular Sequence Data; Mutation; Physiological aspects; rev Gene Products, Human Immunodeficiency Virus - genetics; T cells; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - virology; tat Gene Products, Human Immunodeficiency Virus - genetics; Transmitted/founder virus; Vaccines; Viral fitness; Virology; Virus Replication - genetics
• ISSN: 1742-4690; 1742-4690
• DOI: 10.1186/1742-4690-9-89

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. 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. 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.