title: Viral adaptation to immune selection pressure by HLA class I-restricted CTL responses targeting epitopes in HIV frameshift sequences.
abstract: CD8+ cytotoxic T lymphocyte (CTL)-mediated immune responses to HIV contribute to viral control in vivo. Epitopes encoded by alternative reading frame (ARF) peptides may be targeted by CTLs as well, but their frequency and in vivo relevance are unknown. Using host genetic (human leukocyte antigen [HLA]) and plasma viral sequence information from 765 HIV-infected subjects, we identified 64 statistically significant (q<0.2) associations between specific HLA alleles and sequence polymorphisms in alternate reading frames of gag, pol, and nef that did not affect the regular frame protein sequence. Peptides spanning the top 20 HLA-associated imprints were used to test for ex vivo immune responses in 85 HIV-infected subjects and showed responses to 10 of these ARF peptides. The most frequent response recognized an HLA-A*03-restricted +2 frame-encoded epitope containing a unique A*03-associated polymorphism at position 6. Epitope-specific CTLs efficiently inhibited viral replication in vitro when viruses containing the wild-type sequence but not the observed polymorphism were tested. Mutating alternative internal start codons abrogated the CTL-mediated inhibition of viral replication. These data indicate that responses to ARF-encoded HIV epitopes are induced during natural infection, can contribute to viral control in vivo, and drive viral evolution on a population level.
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, Boston, MA 02129, USA.
authors.forename: Christoph T
authors.initials: CT
authors.lastname: Berger
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Chanson J
authors.initials: CJ
authors.lastname: Brumme
authors.forename: Kari L
authors.initials: KL
authors.lastname: Hartman
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.forename: Leah M
authors.initials: LM
authors.lastname: Henry
authors.forename: Pamela C
authors.initials: PC
authors.lastname: Rosato
authors.forename: Alicja
authors.initials: A
authors.lastname: Piechocka-Trocha
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018387:Codon, Initiator / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D019143:Evolution, Molecular; D005260:Female; D016368:Frameshift Mutation / Q000276:immunology; D006678:HIV / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology*; D015791:HLA-A3 Antigen; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D008297:Male; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D011110:Polymorphism, Genetic / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
chemical_list: D018387:Codon, Initiator; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C487960:HLA-A*03 antigen; D015791:HLA-A3 Antigen; D010455:Peptides; D014764:Viral Proteins