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Cell Rep. 2019 Nov 5;29(6):1449-1457.e5. doi: 10.1016/j.celrep.2019.10.007.

Natural HIV-1 Nef Polymorphisms Impair SERINC5 Downregulation Activity.

Author information

1
Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada.
2
Centre de Recherche du CHUM, Montreal, QC, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
3
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.
4
Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
5
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
6
Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Cambridge, MA, USA.
7
Centre de Recherche du CHUM, Montreal, QC, Canada; Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada; Department of Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, QC, Canada.
8
Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada.
9
Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada. Electronic address: mark_brockman@sfu.ca.

Abstract

HIV-1 Nef enhances virion infectivity by counteracting host restriction factor SERINC5; however, the impact of natural Nef polymorphisms on this function is largely unknown. We characterize SERINC5 downregulation activity of 91 primary HIV-1 subtype B nef alleles, including isolates from 45 elite controllers and 46 chronic progressors. Controller-derived Nef clones display lower ability to downregulate SERINC5 (median 80% activity) compared with progressor-derived clones (median 96% activity) (p = 0.0005). We identify 18 Nef polymorphisms associated with differential function, including two CTL escape mutations that contribute to lower SERINC5 downregulation: K94E, driven by HLA-B08, and H116N, driven by the protective allele HLA-B57. HIV-1 strains encoding Nef K94E and/or H116N display lower infectivity and replication capacity in the presence of SERINC5. Our results demonstrate that natural polymorphisms in HIV-1 Nef can impair its ability to internalize SERINC5, indicating that variation in this recently described function may contribute to differences in viral pathogenesis.

KEYWORDS:

HIV-1 Nef; elite controllers; host restriction; serine incorporator; viral infectivity; viral pathogenesis

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