title: Genetic determinants of Nef-mediated CD4 and HLA class I down-regulation differences between HIV-1 subtypes B and C.
abstract: BACKGROUND
  HIV-1 subtype C Nef sequences have a significantly lower ability overall to down-regulate CD4 and HLA-I than subtype B Nef sequences. Here we investigated whether Nef amino acids differing in frequency between HIV-1 subtypes B and C explain lower CD4 and HLA-I down-regulation ability of subtype C.
  
  
  RESULTS
  Subtype-specific mutations were introduced into representative subtype B and C Nef sequences and the CD4 and HLA-I down-regulation ability of these mutants was measured by flow cytometry in a CD4+ T cell line. Subtype C consensus 20I and subtype B consensus 20M reduced and increased HLA-I down-regulation respectively, and the S88G immune escape mutation (which is significantly more frequent in subtype C than subtype B) reduced CD4 and HLA-I down-regulation.
  
  
  CONCLUSIONS
  Our data suggest that these subtype-specific differences may partly contribute to inter-subtype functional differences, and identification of an immune escape mutation - S88G - that impairs Nef function is of relevance to vaccine design.
authors.affiliation: HIV Pathogenesis Programme, University of KwaZulu-Natal, 719 Umbilo Road, Durban, 4013, South Africa. mannj@ukzn.ac.za.|KwaZulu-Natal Research Institute for Tuberculosis and HIV, University of KwaZulu-Natal, Durban, 4001, South Africa. mannj@ukzn.ac.za.
authors.forename: Jaclyn K
authors.initials: JK
authors.lastname: Mann
authors.affiliation: HIV Pathogenesis Programme, University of KwaZulu-Natal, 719 Umbilo Road, Durban, 4013, South Africa. salehaomarjee@gmail.com.|KwaZulu-Natal Research Institute for Tuberculosis and HIV, University of KwaZulu-Natal, Durban, 4001, South Africa. salehaomarjee@gmail.com.
authors.forename: Saleha
authors.initials: S
authors.lastname: Omarjee
authors.affiliation: HIV Pathogenesis Programme, University of KwaZulu-Natal, 719 Umbilo Road, Durban, 4013, South Africa. khumalop@ukzn.ac.za.|KwaZulu-Natal Research Institute for Tuberculosis and HIV, University of KwaZulu-Natal, Durban, 4001, South Africa. khumalop@ukzn.ac.za.
authors.forename: Phumzile
authors.initials: P
authors.lastname: Khumalo
authors.affiliation: HIV Pathogenesis Programme, University of KwaZulu-Natal, 719 Umbilo Road, Durban, 4013, South Africa. ndungu@ukzn.ac.za.|KwaZulu-Natal Research Institute for Tuberculosis and HIV, University of KwaZulu-Natal, Durban, 4001, South Africa. ndungu@ukzn.ac.za.|Ragon Institute of MGH, MIT and Harvard University, Cambridge, MA, 02139, USA. ndungu@ukzn.ac.za.|Max Planck Institute for Infection Biology, Chariteplatz, D-10117, Berlin, Germany. ndungu@ukzn.ac.za.
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
mesh_terms: D019943:Amino Acid Substitution; D015704:CD4 Antigens / Q000032:analysis*; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000821:virology*; D002460:Cell Line; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D005434:Flow Cytometry; D005838:Genotype; D015497:HIV-1 / Q000145:classification / Q000235:genetics / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000032:analysis*; D054884:Host-Pathogen Interactions; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D015395:Histocompatibility Antigens Class I; D012367:RNA, Viral; D054311:nef Gene Products, Human Immunodeficiency Virus; C514837:nef protein, Human immunodeficiency virus 1