title: Central role of reverting mutations in HLA associations with human immunodeficiency virus set point.
abstract: Much uncertainty still exists over what T-cell responses need to be induced by an effective human immunodeficiency virus (HIV) vaccine. Previous studies have hypothesized that the effective CD8(+) T-cell responses are those driving the selection of escape mutations that reduce viral fitness and therefore revert post-transmission. In this study, we adopted a novel approach to define better the role of reverting escape mutations in immune control of HIV infection. This analysis of sequences from 710 study subjects with chronic C-clade HIV type 1 infection demonstrates the importance of mutations that impose a fitness cost in the control of viremia. Consistent with previous studies, the viral set points associated with each HLA-B allele are strongly correlated with the number of Gag-specific polymorphisms associated with the relevant HLA-B allele (r = -0.56, P = 0.0034). The viral set points associated with each HLA-C allele were also strongly correlated with the number of Pol-specific polymorphisms associated with the relevant HLA-C allele (r = -0.67, P = 0.0047). However, critically, both these correlations were dependent solely on the polymorphisms identified as reverting. Therefore, despite the inevitable evolution of viral escape, viremia can be controlled through the selection of mutations that are detrimental to viral fitness. The significance of these results is in highlighting the rationale for an HIV vaccine that can induce these broad responses.
authors.affiliation: Department of Paediatrics, Peter Medawar Building for Pathogen Research, United Kingdom. p.matthews@doctors.org.uk
authors.forename: Philippa C
authors.initials: PC
authors.lastname: Matthews
authors.forename: Andrew
authors.initials: A
authors.lastname: Prendergast
authors.forename: Alasdair
authors.initials: A
authors.lastname: Leslie
authors.forename: Hayley
authors.initials: H
authors.lastname: Crawford
authors.forename: Rebecca
authors.initials: R
authors.lastname: Payne
authors.forename: Christine
authors.initials: C
authors.lastname: Rousseau
authors.forename: Morgane
authors.initials: M
authors.lastname: Rolland
authors.forename: Isobella
authors.initials: I
authors.lastname: Honeyborne
authors.forename: Jonathan
authors.initials: J
authors.lastname: Carlson
authors.forename: Carl
authors.initials: C
authors.lastname: Kadie
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Karen
authors.initials: K
authors.lastname: Bishop
authors.forename: Nonkululeko
authors.initials: N
authors.lastname: Mlotshwa
authors.forename: James I
authors.initials: JI
authors.lastname: Mullins
authors.forename: Hoosen
authors.initials: H
authors.lastname: Coovadia
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D015331:Cohort Studies; D005787:Gene Frequency; D015683:Gene Products, gag / Q000276:immunology; D015693:Gene Products, nef / Q000276:immunology; D015684:Gene Products, pol / Q000276:immunology; D015658:HIV Infections / Q000097:blood* / Q000276:immunology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D006680:HLA Antigens / Q000097:blood* / Q000145:classification / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D012641:Selection, Genetic; D017423:Sequence Analysis, RNA; D019562:Viral Load / Q000379:methods
chemical_list: D015683:Gene Products, gag; D015693:Gene Products, nef; D015684:Gene Products, pol; D006680:HLA Antigens; D012367:RNA, Viral