title: Nef-mediated down-regulation of CD4 and HLA class I in HIV-1 subtype C infection: association with disease progression and influence of immune pressure.
abstract: Nef plays a major role in HIV-1 pathogenicity. We studied HIV-1 subtype C infected individuals in acute/early (n = 120) or chronic (n = 207) infection to investigate the relationship between Nef-mediated CD4/HLA-I down-regulation activities and disease progression, and the influence of immune-driven sequence variation on these Nef functions. A single Nef sequence per individual was cloned into an expression plasmid, followed by transfection of a T cell line and measurement of CD4 and HLA-I expression. In early infection, a trend of higher CD4 down-regulation ability correlating with higher viral load set point was observed (r = 0.19, p = 0.05), and higher HLA-I down-regulation activity was significantly associated with faster rate of CD4 decline (p = 0.02). HLA-I down-regulation function correlated inversely with the number HLA-associated polymorphisms previously associated with reversion in the absence of the selecting HLA allele (r = -0.21, p = 0.0002). These data support consideration of certain Nef regions in HIV-1 vaccine strategies designed to attenuate the infection course.
authors.affiliation: HIV Pathogenesis Programme, University of KwaZulu-Natal, 719 Umbilo Road, Durban 4001, South Africa; KwaZulu-Natal Research Institute for Tuberculosis and HIV, University of KwaZulu-Natal, Durban 4001, South Africa.
authors.forename: Jaclyn K
authors.initials: JK
authors.lastname: Mann
authors.affiliation: HIV Pathogenesis Programme, University of KwaZulu-Natal, 719 Umbilo Road, Durban 4001, South Africa; KwaZulu-Natal Research Institute for Tuberculosis and HIV, University of KwaZulu-Natal, Durban 4001, South Africa; Institute of Infectious Disease and Molecular Medicine, and the Division of Medical Virology, University of Cape Town and National Health Laboratory Services, Cape Town 7925, South Africa.
authors.forename: Denis
authors.initials: D
authors.lastname: Chopera
authors.affiliation: HIV Pathogenesis Programme, University of KwaZulu-Natal, 719 Umbilo Road, Durban 4001, South Africa; KwaZulu-Natal Research Institute for Tuberculosis and HIV, University of KwaZulu-Natal, Durban 4001, South Africa.
authors.forename: Saleha
authors.initials: S
authors.lastname: Omarjee
authors.affiliation: Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6.
authors.forename: Xiaomei T
authors.initials: XT
authors.lastname: Kuang
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada V5A 1S6.
authors.forename: Anh Q
authors.initials: AQ
authors.lastname: Le
authors.affiliation: Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6.
authors.forename: Gursev
authors.initials: G
authors.lastname: Anmole
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada V5A 1S6.
authors.forename: Ryan
authors.initials: R
authors.lastname: Danroth
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada V5A 1S6.
authors.forename: Philip
authors.initials: P
authors.lastname: Mwimanzi
authors.affiliation: Medical Research Council, Biostatistics Unit, Durban 4001, South Africa.
authors.forename: Tarylee
authors.initials: T
authors.lastname: Reddy
authors.affiliation: Microsoft Research, Los Angeles, CA 90024, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Carlson
authors.affiliation: HIV Pathogenesis Programme, University of KwaZulu-Natal, 719 Umbilo Road, Durban 4001, South Africa; KwaZulu-Natal Research Institute for Tuberculosis and HIV, University of KwaZulu-Natal, Durban 4001, South Africa.
authors.forename: Mopo
authors.initials: M
authors.lastname: Radebe
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom; Ragon Institute of MGH, MIT and Harvard University, Cambridge, MA 02139, USA.
authors.forename: Philip J R
authors.initials: PJR
authors.lastname: Goulder
authors.affiliation: Ragon Institute of MGH, MIT and Harvard University, Cambridge, MA 02139, USA; Massachusetts General Hospital and Harvard University, Boston, MA 02114, USA; Howard Hughes Medical Research Institute, Chevy Chase, MD 20815, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban 4001, South Africa.
authors.forename: Salim
authors.initials: S
authors.lastname: Abdool Karim
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA; Botswana-Harvard School of Public Health AIDS Initiative Partnership for HIV Research and Education, P/Bag BO 320, Gaborone, Botswana.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Novitsky
authors.affiliation: Institute of Infectious Disease and Molecular Medicine, and the Division of Medical Virology, University of Cape Town and National Health Laboratory Services, Cape Town 7925, South Africa.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Williamson
authors.affiliation: Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6; Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada V5A 1S6; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada V6Z 1Y6.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada V5A 1S6; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada V6Z 1Y6.
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.affiliation: HIV Pathogenesis Programme, University of KwaZulu-Natal, 719 Umbilo Road, Durban 4001, South Africa; KwaZulu-Natal Research Institute for Tuberculosis and HIV, University of KwaZulu-Natal, Durban 4001, South Africa; Ragon Institute of MGH, MIT and Harvard University, Cambridge, MA 02139, USA; Max Planck Institute for Infection Biology, Chariteplatz, D-10117 Berlin, Germany. Electronic address: ndungu@ukzn.ac.za.
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
mesh_terms: D015496:CD4-Positive T-Lymphocytes; D005786:Gene Expression Regulation / Q000276:immunology*; D005805:Genes, MHC Class I / Q000235:genetics / Q000502:physiology*; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1
keywords: CD4 down-regulation; HIV-1 Nef; HIV-1 disease progression; HIV-1 subtype C; HLA-I down-regulation; HLA-associated polymorphisms; Immune evasion