Research reported in this publication was supported by 1) the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number UM1AI126617 (the Martin Delaney BELIEVE collaboratory), with co- funding support from the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Institute of Neurological Disorders and Stroke; 2) a 2017 award from the District of Columbia Center for AIDS Research, an NIH funded program (AI117970), which is supported by the following NIH Co-Funding and Participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, NIGMS, NIDDK, and OAR; 3) federal funds from the Frederick National Laboratory for Cancer Research, and the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E; 4) the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research; 5) a Wellcome Trust Senior Research Fellowship (WT098049AIA) and an MRC UK project grant (G0801937); 6) a project grant from the Canadian Institutes of Health Research (PJT-148621), Canada Research Chair in Viral Pathogenesis and Immunity, and Scholar Award from the Michael Smith Foundation for Health Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
HIV -- Research, Pathogens
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.
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Bachtel, N. D., Umviligihozo, G., Pickering, S., Mota, T., Liang, H., Del Prete, G. Q., ... & Neil, S. (2018). HLA-C downregulation by HIV-1 adapts to host HLA genotype. PLoS pathogens, 14(9), e1007257.