Convergent Evolution of HLA-C Downmodulation in HIV-1 and HIV-2

mBio. 2020 Jul 14;11(4):e00782-20. doi: 10.1128/mBio.00782-20.


HLA-C-mediated antigen presentation induces the killing of human immunodeficiency virus (HIV)-infected CD4+ T cells by cytotoxic T lymphocytes (CTLs). To evade killing, many HIV-1 group M strains decrease HLA-C surface levels using their accessory protein Vpu. However, some HIV-1 group M isolates lack this activity, possibly to prevent the activation of natural killer (NK) cells. Analyzing diverse primate lentiviruses, we found that Vpu-mediated HLA-C downregulation is not limited to pandemic group M but is also found in HIV-1 groups O and P as well as several simian immunodeficiency viruses (SIVs). We show that Vpu targets HLA-C primarily at the protein level, independently of its ability to suppress NF-κB-driven gene expression, and that in some viral lineages, HLA-C downregulation may come at the cost of efficient counteraction of the restriction factor tetherin. Remarkably, HIV-2, which does not carry a vpu gene, uses its accessory protein Vif to decrease HLA-C surface expression. This Vif activity requires intact binding sites for the Cullin5/Elongin ubiquitin ligase complex but is separable from its ability to counteract APOBEC3G. Similar to HIV-1 Vpu, the degree of HIV-2 Vif-mediated HLA-C downregulation varies considerably among different virus isolates. In agreement with opposing selection pressures in vivo, we show that the reduction of HLA-C surface levels by HIV-2 Vif is accompanied by increased NK cell-mediated killing. In summary, our results highlight the complex role of HLA-C in lentiviral infections and demonstrate that HIV-1 and HIV-2 have evolved at least two independent mechanisms to decrease HLA-C levels on infected cells.IMPORTANCE Genome-wide association studies suggest that HLA-C expression is a major determinant of viral load set points and CD4+ T cell counts in HIV-infected individuals. On the one hand, efficient HLA-C expression enables the killing of infected cells by cytotoxic T lymphocytes (CTLs). On the other hand, HLA-C sends inhibitory signals to natural killer (NK) cells and enhances the infectivity of newly produced HIV particles. HIV-1 group M viruses modulate HLA-C expression using the accessory protein Vpu, possibly to balance CTL- and NK cell-mediated immune responses. Here, we show that the second human immunodeficiency virus, HIV-2, can use its accessory protein Vif to evade HLA-C-mediated restriction. Furthermore, our mutational analyses provide insights into the underlying molecular mechanisms. In summary, our results reveal how the two human AIDS viruses modulate HLA-C, a key component of the antiviral immune response.

Keywords: HIV-1; HIV-2; HLA-C; SIV; Vif; Vpu.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / virology
  • Evolution, Molecular*
  • HEK293 Cells
  • HIV Infections / immunology
  • HIV Infections / virology
  • HIV-1 / classification
  • HIV-1 / genetics*
  • HIV-1 / immunology
  • HIV-2 / genetics*
  • HIV-2 / immunology
  • HLA-C Antigens / genetics*
  • Host-Pathogen Interactions / immunology
  • Human Immunodeficiency Virus Proteins / genetics*
  • Humans
  • Killer Cells, Natural / immunology
  • T-Lymphocytes, Cytotoxic / immunology
  • Viral Regulatory and Accessory Proteins / genetics*
  • vif Gene Products, Human Immunodeficiency Virus / genetics*
  • vif Gene Products, Human Immunodeficiency Virus / immunology


  • HLA-C Antigens
  • Human Immunodeficiency Virus Proteins
  • Viral Regulatory and Accessory Proteins
  • vif Gene Products, Human Immunodeficiency Virus
  • vif protein, Human immunodeficiency virus 2
  • vpu protein, Human immunodeficiency virus 1