Nef-Specific CD8+ T Cell Responses Contribute to HIV-1 Immune Control

• Published in: PloS one Vol. 8; no. 9; p. e73117
• Main Authors: Adland, Emily, Carlson, Jonathan M., Paioni, Paolo, Kløverpris, Henrik, Shapiro, Roger, Ogwu, Anthony, Riddell, Lynn, Luzzi, Graz, Chen, Fabian, Balachandran, Thambiah, Heckerman, David, Stryhn, Anette, Edwards, Anne, Ndung’u, Thumbi, Walker, Bruce D., Buus, Søren, Goulder, Philip, Matthews, Philippa C.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.09.2013; Public Library of Science (PLoS)
• Subjects: Acquired immune deficiency syndrome; Adult; AIDS; Alleles; Amino Acid Sequence; Amino acids; Analysis; Binding sites; CD8 antigen; CD8 lymphocytes; CD8-Positive T-Lymphocytes - immunology; Chronic infection; Conserved Sequence; Control; Cytotoxicity; Development and progression; Disease control; Enzyme-linked immunosorbent assay; Epitopes; Evolution, Molecular; Fitness; Gag protein; Genetic aspects; Health aspects; Health sciences; Histocompatibility antigen HLA; HIV; HIV infections; HIV-1 - genetics; HIV-1 - immunology; HIV-1 - metabolism; HIV-1 - physiology; HLA-B Antigens - metabolism; Hospitals; Human immunodeficiency virus; Humans; Hypotheses; Immune response; Immunization; Immunogenicity; Immunology; Infections; Interferon; Laboratories; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Medawar, Peter; Medical research; Medicine; Molecular Sequence Data; Mutation; nef Gene Products, Human Immunodeficiency Virus - chemistry; nef Gene Products, Human Immunodeficiency Virus - genetics; nef Gene Products, Human Immunodeficiency Virus - immunology; nef Gene Products, Human Immunodeficiency Virus - metabolism; Nef protein; Pathogenesis; Peptides; Physiological aspects; Polymorphism, Genetic; Proteins; Selection, Genetic; Viral Load - immunology; Viremia; Viruses; United States; United Kingdom; Los Angeles California; South Africa; California; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0073117

Recent studies in the SIV-macaque model of HIV infection suggest that Nef-specific CD8+ T-cell responses may mediate highly effective immune control of viraemia. In HIV infection Nef recognition dominates in acute infection, but in large cohort studies of chronically infected subjects, breadth of T cell responses to Nef has not been correlated with significant viraemic control. Improved disease outcomes have instead been associated with targeting Gag and, in some cases, Pol. However analyses of the breadth of Nef-specific T cell responses have been confounded by the extreme immunogenicity and multiple epitope overlap within the central regions of Nef, making discrimination of distinct responses impossible via IFN-gamma ELISPOT assays. Thus an alternative approach to assess Nef as an immune target is needed. Here, we show in a cohort of >700 individuals with chronic C-clade infection that >50% of HLA-B-selected polymorphisms within Nef are associated with a predicted fitness cost to the virus, and that HLA-B alleles that successfully drive selection within Nef are those linked with lower viral loads. Furthermore, the specific CD8+ T cell epitopes that are restricted by protective HLA Class I alleles correspond substantially to effective SIV-specific epitopes in Nef. Distinguishing such individual HIV-specific responses within Nef requires specific peptide-MHC I tetramers. Overall, these data suggest that CD8+ T cell targeting of certain specific Nef epitopes contributes to HIV suppression. These data suggest that a re-evaluation of the potential use of Nef in HIV T-cell vaccine candidates would be justified.