Resistance of major histocompatibility complex class B (MHC-B) to Nef-mediated downregulation relative to that of MHC-A is conserved among primate lentiviruses and influences antiviral T cell responses in HIV-1-infected individuals

Francis Mwimanzi, Mako Toyoda, Macdonald Mahiti, Jaclyn K. Mann, Jeffrey N. Martin, David Bangsberg, Mark A. Brockman, Philip Goulder, Frank Kirchhoff, Zabrina L. Brumme, Thumbi Ndung'u, Takamasa Ueno

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Patient-derived HIV-1 subtype B Nef clones downregulate HLA-A more efficiently than HLA-B. However, it remains unknown whether this property is common to Nef proteins across primate lentiviruses and how antiviral immune responses may be affected. We examined 263 Nef clones from diverse primate lentiviruses including different pandemic HIV-1 group M subtypes for their ability to downregulate major histocompatibility complex class A (MHC-A) and MHC-B from the cell surface. Though lentiviral Nef proteins differed markedly in their absolute MHC-A and MHC-B downregulation abilities, all lentiviral Nef lineages downregulated MHC-A, on average, 11 to 32% more efficiently than MHC-B. Nef genotype/phenotype analyses in a cohort of HIV-1 subtype C-infected patients (n = 168), together with site-directed mutagenesis, revealed Nef position 9 as a subtype-specific determinant of differential HLA-A versus HLA-B downregulation activity. Nef clones harboring nonconsensus variants at codon 9 downregulated HLA-B (though not HLA-A) significantly better than those harboring the consensus sequence at this site, resulting in reduced recognition of infected target cells by HIV-1-specific CD8+ effector cells in vitro. Among persons expressing protective HLA class I alleles, carriage of Nef codon 9 variants was also associated with reduced ex vivo HIV-specific T cell responses. Our results demonstrate that Nef's inferior ability to downregulate MHC-B compared to that of MHC-A is conserved across primate lentiviruses and suggest that this property influences antiviral cellular immune responses.

Original languageEnglish (US)
Article numbere01409-17
JournalJournal of virology
Volume92
Issue number1
DOIs
StatePublished - Jan 1 2018

Keywords

  • HLA
  • Human immunodeficiency virus
  • Immune evasion
  • Lentiviruses
  • Nef

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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