title: Selective escape from CD8+ T-cell responses represents a major driving force of human immunodeficiency virus type 1 (HIV-1) sequence diversity and reveals constraints on HIV-1 evolution.
abstract: The sequence diversity of human immunodeficiency virus type 1 (HIV-1) represents a major obstacle to the development of an effective vaccine, yet the forces impacting the evolution of this pathogen remain unclear. To address this issue we assessed the relationship between genome-wide viral evolution and adaptive CD8+ T-cell responses in four clade B virus-infected patients studied longitudinally for as long as 5 years after acute infection. Of the 98 amino acid mutations identified in nonenvelope antigens, 53% were associated with detectable CD8+ T-cell responses, indicative of positive selective immune pressures. An additional 18% of amino acid mutations represented substitutions toward common clade B consensus sequence residues, nine of which were strongly associated with HLA class I alleles not expressed by the subjects and thus indicative of reversions of transmitted CD8 escape mutations. Thus, nearly two-thirds of all mutations were attributable to CD8+ T-cell selective pressures. A closer examination of CD8 escape mutations in additional persons with chronic disease indicated that not only did immune pressures frequently result in selection of identical amino acid substitutions in mutating epitopes, but mutating residues also correlated with highly polymorphic sites in both clade B and C viruses. These data indicate a dominant role for cellular immune selective pressures in driving both individual and global HIV-1 evolution. The stereotypic nature of acquired mutations provides support for biochemical constraints limiting HIV-1 evolution and for the impact of CD8 escape mutations on viral fitness.
authors.affiliation: Howard Hughes Medical Institute, Partners AIDS Research Center, and Infectious Disease Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: Shaun C
authors.initials: SC
authors.lastname: Geer
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Kalife
authors.forename: Corey
authors.initials: C
authors.lastname: Moore
authors.forename: Kristin M
authors.initials: KM
authors.lastname: O'sullivan
authors.forename: Ivna
authors.initials: I
authors.lastname: Desouza
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Feeney
authors.forename: Robert L
authors.initials: RL
authors.lastname: Eldridge
authors.forename: Erica L
authors.initials: EL
authors.lastname: Maier
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Lahaie
authors.forename: Laura
authors.initials: L
authors.lastname: Reyor
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Tanzi
authors.forename: Mary N
authors.initials: MN
authors.lastname: Johnston
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Rika
authors.initials: R
authors.lastname: Draenert
authors.forename: Jurgen K
authors.initials: JK
authors.lastname: Rockstroh
authors.forename: Heiko
authors.initials: H
authors.lastname: Jessen
authors.forename: Eric S
authors.initials: ES
authors.lastname: Rosenberg
authors.forename: Simon A
authors.initials: SA
authors.lastname: Mallal
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
mesh_terms: D000208:Acute Disease; D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D015331:Cohort Studies; D018984:Epitopes, T-Lymphocyte / Q000235:genetics; D019143:Evolution, Molecular; D005805:Genes, MHC Class I / Q000235:genetics; D005858:Germany; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D018655:Lymphocyte Count; D008969:Molecular Sequence Data; D009154:Mutation / Q000276:immunology*; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D016415:Sequence Alignment; D014481:United States
chemical_list: D018984:Epitopes, T-Lymphocyte