title: Marked epitope- and allele-specific differences in rates of mutation in human immunodeficiency type 1 (HIV-1) Gag, Pol, and Nef cytotoxic T-lymphocyte epitopes in acute/early HIV-1 infection.
abstract: During acute human immunodeficiency virus type 1 (HIV-1) infection, early host cellular immune responses drive viral evolution. The rates and extent of these mutations, however, remain incompletely characterized. In a cohort of 98 individuals newly infected with HIV-1 subtype B, we longitudinally characterized the rates and extent of HLA-mediated escape and reversion in Gag, Pol, and Nef using a rational definition of HLA-attributable mutation based on the analysis of a large independent subtype B data set. We demonstrate rapid and dramatic HIV evolution in response to immune pressures that in general reflect established cytotoxic T-lymphocyte (CTL) response hierarchies in early infection. On a population level, HLA-driven evolution was observed in approximately 80% of published CTL epitopes. Five of the 10 most rapidly evolving epitopes were restricted by protective HLA alleles (HLA-B*13/B*51/B*57/B*5801; P = 0.01), supporting the importance of a strong early CTL response in HIV control. Consistent with known fitness costs of escape, B*57-associated mutations in Gag were among the most rapidly reverting positions upon transmission to non-B*57-expressing individuals, whereas many other HLA-associated polymorphisms displayed slow or negligible reversion. Overall, an estimated minimum of 30% of observed substitutions in Gag/Pol and 60% in Nef were attributable to HLA-associated escape and reversion events. Results underscore the dominant role of immune pressures in driving early within-host HIV evolution. Dramatic differences in escape and reversion rates across codons, genes, and HLA restrictions are observed, highlighting the complexity of viral adaptation to the host immune response.
authors.affiliation: Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. zbrumme@partners.org
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.forename: Chanson J
authors.initials: CJ
authors.lastname: Brumme
authors.forename: Jonathan
authors.initials: J
authors.lastname: Carlson
authors.forename: Hendrik
authors.initials: H
authors.lastname: Streeck
authors.forename: Mina
authors.initials: M
authors.lastname: John
authors.forename: Quentin
authors.initials: Q
authors.lastname: Eichbaum
authors.forename: Brian L
authors.initials: BL
authors.lastname: Block
authors.forename: Brett
authors.initials: B
authors.lastname: Baker
authors.forename: Carl
authors.initials: C
authors.lastname: Kadie
authors.forename: Martin
authors.initials: M
authors.lastname: Markowitz
authors.forename: Heiko
authors.initials: H
authors.lastname: Jessen
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Kelleher
authors.forename: Eric
authors.initials: E
authors.lastname: Rosenberg
authors.forename: John
authors.initials: J
authors.lastname: Kaldor
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yuki
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
mesh_terms: D000208:Acute Disease; D000483:Alleles; D000595:Amino Acid Sequence; D018984:Epitopes, T-Lymphocyte / Q000235:genetics*; D019143:Evolution, Molecular; D015750:Genes, gag / Q000235:genetics; D015754:Genes, nef / Q000235:genetics; D015751:Genes, pol / Q000235:genetics; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000235:genetics* / Q000276:immunology; D015235:HLA-B Antigens / Q000378:metabolism; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D015235:HLA-B Antigens; D054298:Human Immunodeficiency Virus Proteins