HLA-C downregulation by HIV-1 adapts to host HLA genotype

• Published in: PLoS pathogens 2018-09, Vol.14 (9), p.e1007257
• Main Authors: Bachtel, Nathaniel D, Umviligihozo, Gisele, Pickering, Suzanne, Mota, Talia M, Liang, Hua, Del Prete, Gregory Q, Chatterjee, Pramita, Lee, Guinevere Q, Thomas, Rasmi, Brockman, Mark A, Neil, Stuart, Carrington, Mary, Bwana, Bosco, Bangsberg, David R, Martin, Jeffrey N, Kallas, Esper G, Donini, Camila S, Cerqueira, Natalia B, O'Doherty, Una T, Hahn, Beatrice H, Jones, R Brad, Brumme, Zabrina L, Nixon, Douglas F, Apps, Richard
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Alleles; Amino Acid Sequence; Binding sites; Biology and Life Sciences; Cancer; Chronic infection; Cytotoxicity; Disease Reservoirs - virology; Down-Regulation; Funding; Gene expression; Genetic aspects; Genetic Variation; Genomes; Genotype; Genotypes; Health aspects; Health sciences; Histocompatibility antigen HLA; HIV; HIV Infections - genetics; HIV Infections - immunology; HIV Infections - virology; HIV-1 - immunology; HIV-1 - pathogenicity; HLA antigens; HLA-C Antigens - genetics; Hospitals; Host-Pathogen Interactions - genetics; Host-Pathogen Interactions - immunology; Human immunodeficiency virus; Human Immunodeficiency Virus Proteins - chemistry; Human Immunodeficiency Virus Proteins - genetics; Human Immunodeficiency Virus Proteins - immunology; Humans; Immune Evasion; Immunology; Infections; Infectious diseases; Inflammation; Laboratories; Lymphocytes T; Medical research; Medicine; Medicine and Health Sciences; Peptides; Physical Sciences; Physiological aspects; Preservation; Research and Analysis Methods; Residues; Science programs; Supervision; Therapy; Viral Regulatory and Accessory Proteins - chemistry; Viral Regulatory and Accessory Proteins - genetics; Viral Regulatory and Accessory Proteins - immunology; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007257

HIV-1 can downregulate HLA-C on infected cells, using the viral protein Vpu, and the magnitude of this downregulation varies widely between primary HIV-1 variants. The selection pressures that result in viral downregulation of HLA-C in some individuals, but preservation of surface HLA-C in others are not clear. To better understand viral immune evasion targeting HLA-C, we have characterized HLA-C downregulation by a range of primary HIV-1 viruses. 128 replication competent viral isolates from 19 individuals with effective anti-retroviral therapy, show that a substantial minority of individuals harbor latent reservoir virus which strongly downregulates HLA-C. Untreated infections display no change in HLA-C downregulation during the first 6 months of infection, but variation between viral quasispecies can be detected in chronic infection. Vpu molecules cloned from plasma of 195 treatment naïve individuals in chronic infection demonstrate that downregulation of HLA-C adapts to host HLA genotype. HLA-C alleles differ in the pressure they exert for downregulation, and individuals with higher levels of HLA-C expression favor greater viral downregulation of HLA-C. Studies of primary and mutant molecules identify 5 residues in the transmembrane region of Vpu, and 4 residues in the transmembrane domain of HLA-C, which determine interactions between Vpu and HLA. The observed adaptation of Vpu-mediated downregulation to host genotype indicates that HLA-C alleles differ in likelihood of mediating a CTL response that is subverted by viral downregulation, and that preservation of HLA-C expression is favored in the absence of these responses. Finding that latent reservoir viruses can downregulate HLA-C could have implications for HIV-1 cure therapy approaches in some individuals.