Journal Article

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

Berg, Anna, Perelson, Alan S, Decker, Julie M, Goonetilleke, Nilu, McMichael, Andrew, Bar, Katharine J, Song, Hongshuo, Haynes, Barton F, Ferrari, Guido, Li, Hui, Iyer, Shilpa S, Eudailey, Josh, Pavlicek, Jeffrey W, Hahn, Beatrice H, Drinker, Mark S, Liu, Michael KP, Shaw, George M, Moody, M Anthony, Bhattacharya, Tanmoy, Gao, Feng, Hora, Bhavna, Pickeral, Joy, Cai, Fangping

2012

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acquired immune deficiency syndrome / AIDS / Analysis / Antibodies / Antigenic determinants / Base Sequence / BASIC BIOLOGICAL SCIENCES / Biomedical and Life Sciences / Biomedicine / Cancer Research / 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 / Infectious Diseases / Lymphocytes / Mathematical model / Mathematical models / Medicine / Molecular Sequence Data / Mutation / Physiological aspects / Protein Structure / 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 / Vaccine / Vaccines / Viral fitness / Virology / Virus Replication - genetics / World AIDS Day 2012