title: Evidence of differential HLA class I-mediated viral evolution in functional and accessory/regulatory genes of HIV-1.
abstract: Despite the formidable mutational capacity and sequence diversity of HIV-1, evidence suggests that viral evolution in response to specific selective pressures follows generally predictable mutational pathways. Population-based analyses of clinically derived HIV sequences may be used to identify immune escape mutations in viral genes; however, prior attempts to identify such mutations have been complicated by the inability to discriminate active immune selection from virus founder effects. Furthermore, the association between mutations arising under in vivo immune selection and disease progression for highly variable pathogens such as HIV-1 remains incompletely understood. We applied a viral lineage-corrected analytical method to investigate HLA class I-associated sequence imprinting in HIV protease, reverse transcriptase (RT), Vpr, and Nef in a large cohort of chronically infected, antiretrovirally naïve individuals. A total of 478 unique HLA-associated polymorphisms were observed and organized into a series of "escape maps," which identify known and putative cytotoxic T lymphocyte (CTL) epitopes under selection pressure in vivo. Our data indicate that pathways to immune escape are predictable based on host HLA class I profile, and that epitope anchor residues are not the preferred sites of CTL escape. Results reveal differential contributions of immune imprinting to viral gene diversity, with Nef exhibiting far greater evidence for HLA class I-mediated selection compared to other genes. Moreover, these data reveal a significant, dose-dependent inverse correlation between HLA-associated polymorphisms and HIV disease stage as estimated by CD4(+) T cell count. Identification of specific sites and patterns of HLA-associated polymorphisms across HIV protease, RT, Vpr, and Nef illuminates regions of the genes encoding these products under active immune selection pressure in vivo. The high density of HLA-associated polymorphisms in Nef compared to other genes investigated indicates differential HLA class I-driven evolution in different viral genes. The relationship between HLA class I-associated polymorphisms and lower CD4(+) cell count suggests that immune escape correlates with disease status, supporting an essential role of maintenance of effective CTL responses in immune control of HIV-1. The design of preventative and therapeutic CTL-based vaccine approaches could incorporate information on predictable escape pathways.
authors.affiliation: Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.forename: Chanson J
authors.initials: CJ
authors.lastname: Brumme
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Bette T
authors.initials: BT
authors.lastname: Korber
authors.forename: Marcus
authors.initials: M
authors.lastname: Daniels
authors.forename: Jonathan
authors.initials: J
authors.lastname: Carlson
authors.forename: Carl
authors.initials: C
authors.lastname: Kadie
authors.forename: Tanmoy
authors.initials: T
authors.lastname: Bhattacharya
authors.forename: Celia
authors.initials: C
authors.lastname: Chui
authors.forename: James
authors.initials: J
authors.lastname: Szinger
authors.forename: Theresa
authors.initials: T
authors.lastname: Mo
authors.forename: Robert S
authors.initials: RS
authors.lastname: Hogg
authors.forename: Julio S G
authors.initials: JS
authors.lastname: Montaner
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
mesh_terms: D000595:Amino Acid Sequence; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D019143:Evolution, Molecular; D015967:Gene Expression Regulation, Viral; D005805:Genes, MHC Class I / Q000502:physiology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D011110:Polymorphism, Genetic; D012641:Selection, Genetic; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics* / Q000378:metabolism; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D054298:Human Immunodeficiency Virus Proteins; C094840:MR1 protein, human; D015778:Minor Histocompatibility Antigens; D054334:Viral Regulatory and Accessory Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus; D054325:vpr Gene Products, Human Immunodeficiency Virus