title: Counteraction of HLA-C-mediated immune control of HIV-1 by Nef.
abstract: A host genetic variant (-35C/T) correlates with increased human leukocyte antigen C (HLA-C) expression and improved control of HIV-1. HLA-C-mediated immunity may be particularly protective because HIV-1 is unable to remove HLA-C from the cell surface, whereas it can avoid HLA-A- and HLA-B-mediated immunity by Nef-mediated down-modulation. However, some individuals with the protective -35CC genotype exhibit high viral loads. Here, we investigated whether the ability of HIV-1 to replicate efficiently in the "protective" high-HLA-C-expression host environment correlates with specific functional properties of Nef. We found that high set point viral loads (sVLs) were not associated with the emergence of Nef variants that had acquired the ability to down-modulate HLA-C or were more effective in removing HLA-A and HLA-B from the cell surface. However, in individuals with the protective -35CC genotype we found a significant association between sVLs and the efficiency of Nef-mediated enhancement of virion infectivity and modulation of CD4, CD28, and the major histocompatibility complex class II (MHC-II)-associated invariant chain (Ii), while this was not observed in subjects with the -35TT genotype. Since the latter Nef functions all influence the stimulation of CD4(+) T helper cells by antigen-presenting cells, they may cooperate to affect both the activation status of infected T cells and the generation of an antiviral cytotoxic T-lymphocyte (CTL) response. In comparison, different levels of viremia in individuals with the common -35TT genotype were not associated with differences in Nef function but with differences in HLA-C mRNA expression levels. Thus, while high HLA-C expression may generally facilitate control of HIV-1, Nef may counteract HLA-C-mediated immune control in some individuals indirectly, by manipulating T-cell function and MHC-II antigen presentation.
authors.affiliation: Institute of Molecular Virology, University Hospital of Ulm, Meyerhofstr. 1, 89081 Ulm, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Specht
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.forename: Raquel
authors.initials: R
authors.lastname: Martinez
authors.forename: Jacques
authors.initials: J
authors.lastname: Fellay
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bailes
authors.forename: David T
authors.initials: DT
authors.lastname: Evans
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.forename: Beatrice H
authors.initials: BH
authors.lastname: Hahn
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
authors.forename: Frank
authors.initials: F
authors.lastname: Kirchhoff
mesh_terms: D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D005838:Genotype; D015497:HIV-1 / Q000276:immunology*; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D019562:Viral Load; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology / Q000502:physiology*
chemical_list: D016827:CD8 Antigens; D015236:HLA-C Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D050778:NFATC Transcription Factors; D011993:Recombinant Fusion Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus
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