title: Reversion and T cell escape mutations compensate the fitness loss of a CD8+ T cell escape mutant in their cognate transmitted/founder virus.
abstract: Immune escape mutations that revert back to the consensus sequence frequently occur in newly HIV-1-infected individuals and have been thought to render the viruses more fit. However, their impact on viral fitness and their interaction with other immune escape mutations have not been evaluated in the background of their cognate transmitted/founder (T/F) viral genomes. To precisely determine the role of reversion mutations, we introduced reversion mutations alone or together with CD8+ T cell escape mutations in their unmodified cognate T/F viral genome and determined their impact on viral fitness in primary CD4+ T cells. Two reversion mutations, V247I and I64T, were identified in Gag and Tat, respectively, but neither had measurable effect on the fitness of their cognate T/F virus. The V247I and G248A mutations that were detected before and concurrently with the potent T cell escape mutation T242N, respectively, were selected by early T cell responses. The V247I or the G248A mutation alone partially restored the fitness loss caused by the T242N mutation. Together they could fully restore the fitness of the T242N mutant to the T/F level. These results demonstrate that the fitness loss caused by a T cell escape mutation could be compensated by preexisting or concurrent reversion and other T cell escape mutations. Our findings indicate that the overall viral fitness is modulated by the complex interplay among T cell escape, compensatory and reversion mutations to maintain the balance between immune escape and viral replication capacity.
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Hongshuo
authors.initials: H
authors.lastname: Song
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Bhavna
authors.initials: B
authors.lastname: Hora
authors.affiliation: Theoretical Division, Los Alamos National laboratory, Los Alamos, New Mexico, United States of America; Santa Fe Institute, Santa Fe, New Mexico, United States of America.
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Bhattacharya
authors.affiliation: Weatherall Institute of molecular Medicine, University of Oxford, Oxford, England, United Kingdom.
authors.forename: Nilu
authors.initials: N
authors.lastname: Goonetilleke
authors.affiliation: Weatherall Institute of molecular Medicine, University of Oxford, Oxford, England, United Kingdom.
authors.forename: Michael K P
authors.initials: MK
authors.lastname: Liu
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wiehe
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Shilpa S
authors.initials: SS
authors.lastname: Iyer
authors.affiliation: Weatherall Institute of molecular Medicine, University of Oxford, Oxford, England, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
authors.affiliation: Theoretical Division, Los Alamos National laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
mesh_terms: D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D017931:DNA Primers / Q000235:genetics; D058501:Enzyme-Linked Immunospot Assay; D056084:Genetic Fitness / Q000235:genetics*; D016679:Genome, Viral / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D057131:Immune Evasion / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014779:Virus Replication / Q000235:genetics / Q000502:physiology
chemical_list: D017931:DNA Primers