title: Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection.
abstract: HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-naïve, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004). The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001), but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007). Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002). In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, yet to be fully defined, are predominantly responsible for pediatric non-progression.
authors.affiliation: Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom.
authors.forename: Emily
authors.initials: E
authors.lastname: Adland
authors.affiliation: Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom.
authors.forename: Paolo
authors.initials: P
authors.lastname: Paioni
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Christina
authors.initials: C
authors.lastname: Thobakgale
authors.affiliation: Paediatric Department, Kimberley Hospital, Northern Cape, South Africa.
authors.forename: Leana
authors.initials: L
authors.lastname: Laker
authors.affiliation: Paediatric Department, Kimberley Hospital, Northern Cape, South Africa.
authors.forename: Luisa
authors.initials: L
authors.lastname: Mori
authors.affiliation: Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom; HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenchhoff
authors.affiliation: Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Csala
authors.affiliation: Department of Paediatric Infectious Diseases, Great Ormond St Hospital for Children, London, United Kingdom.
authors.forename: Margaret
authors.initials: M
authors.lastname: Clapson
authors.affiliation: Department of Paediatric Infectious Diseases, Great Ormond St Hospital for Children, London, United Kingdom.
authors.forename: Jacquie
authors.initials: J
authors.lastname: Flynn
authors.affiliation: Department of Paediatric Infectious Diseases, Great Ormond St Hospital for Children, London, United Kingdom.
authors.forename: Vas
authors.initials: V
authors.lastname: Novelli
authors.affiliation: The Institute for Emerging Infections, The Oxford Martin School, University of Oxford, Oxford, United Kingdom; Nuffield Department of Medicine, University of Oxford, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom; Oxford National Institute of Health Research, Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: Jacob
authors.initials: J
authors.lastname: Hurst
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Naidoo
authors.affiliation: Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana.
authors.forename: Roger
authors.initials: R
authors.lastname: Shapiro
authors.affiliation: The Institute for Emerging Infections, The Oxford Martin School, University of Oxford, Oxford, United Kingdom; Nuffield Department of Medicine, University of Oxford, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom.
authors.forename: Kuan-Hsiang Gary
authors.initials: KH
authors.lastname: Huang
authors.affiliation: The Institute for Emerging Infections, The Oxford Martin School, University of Oxford, Oxford, United Kingdom; Nuffield Department of Medicine, University of Oxford, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom; Oxford National Institute of Health Research, Biomedical Research Centre, Oxford, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Frater
authors.affiliation: Centre for Paediatrics, Blizard Institute, Queen Mary University of London, London, United Kingdom; Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe.
authors.forename: Andrew
authors.initials: A
authors.lastname: Prendergast
authors.affiliation: AIDS Research Institute IrsiCaixa, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Badalona, Barcelona, Spain.
authors.forename: Julia G
authors.initials: JG
authors.lastname: Prado
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa; The Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), and Harvard University, Boston, Massachusetts, United States of America; KwaZulu-Natal Research Institute for Tuberculosis and HIV, University of KwaZulu-Natal, Durban, South Africa; Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.affiliation: HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa; The Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), and Harvard University, Boston, Massachusetts, United States of America.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: The Ragon Institute of Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), and Harvard University, Boston, Massachusetts, United States of America; Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.affiliation: Paediatric Department, Kimberley Hospital, Northern Cape, South Africa.
authors.forename: Pieter
authors.initials: P
authors.lastname: Jooste
authors.affiliation: Department of Paediatrics, University of Oxford, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom; HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa; Department of Paediatric Infectious Diseases, Great Ormond St Hospital for Children, London, United Kingdom.
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
mesh_terms: D000328:Adult; D002648:Child; D015331:Cohort Studies; D018450:Disease Progression; D015658:HIV Infections / Q000235:genetics*; D015497:HIV-1 / Q000502:physiology*; D006680:HLA Antigens / Q000235:genetics*; D006801:Humans; D016133:Polymerase Chain Reaction; D014779:Virus Replication / Q000235:genetics*
chemical_list: D006680:HLA Antigens