Date Published: September 4, 2018
Publisher: Public Library of Science
Author(s): Nathaniel D. Bachtel, Gisele Umviligihozo, Suzanne Pickering, Talia M. Mota, Hua Liang, Gregory Q. Del Prete, Pramita Chatterjee, Guinevere Q. Lee, Rasmi Thomas, Mark A. Brockman, Stuart Neil, Mary Carrington, Bosco Bwana, David R. Bangsberg, Jeffrey N. Martin, Esper G. Kallas, Camila S. Donini, Natalia B. Cerqueira, Una T. O’Doherty, Beatrice H. Hahn, R. Brad Jones, Zabrina L. Brumme, Douglas F. Nixon, Richard Apps, David T. Evans.
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.
Human Leukocyte Antigen class-I (HLA-I) molecules present peptides from intracellular proteins at the cell surface. Classical HLA-I molecules are highly polymorphic and expressed from three loci, HLA-A,—B and—C, which differ in some respects. Polymorphism is most pronounced for HLA-B, and HLA-A/B are expressed at around 10-fold higher levels than HLA-C at the cell surface [1,2]. In the event of HIV-1 infection, HLA-A/B/C proteins can all present viral peptides which are recognized by CD8+ T cells, and result in the triggering of effector responses including target cell killing. Several lines of evidence provide unambiguous support for a critical role of CD8+ T cell responses in partial control of HIV-1 infection: the emergence of cytotoxic T lymphocytes (CTL) coincides with reduction in viral load after acute infection [3–5], HLA-I alleles associate with outcomes of HIV-1 infection or viral sequence adaptation [6–9], and CTL can eliminate infected cells in vitro . Many pathogens evade CTLs by disrupting HLA expression, but this can incur recognition by innate immune cells. Natural Killer (NK) cells are regulated by inhibitory receptors for self HLA-I molecules, such as inhibitory killer immunoglobulin-like receptors (KIR). Cells with decreased HLA expression fail to ligate these inhibitory receptors, resulting in NK activation and cytotoxicity . Associations between KIR alleles and viral load provide evidence that NK cells can influence the outcome of HIV-1 infection in vivo, and NK cells can be observed to respond to HIV-1 infected cells in vitro [12–14].
Until recently it was believed that HIV-1 Nef subverted both CTL and NK cell immunity by downregulating the dominant CTL ligands HLA-A and -B, but preserving expression of HLA-C and HLA-E which serve as ligands for KIR2DL and NKG2A receptors that inhibit NK cells [16,18]. This understanding was modified by our finding that primary strains of HIV-1 can also downregulate HLA-C using the viral Vpu protein . A major difference between the viral modulation of HLA-A/B compared to HLA-C, is that most HIV-1 strains downregulate HLA-A/B relatively well whereas HLA-C downregulation varies widely. The consequences resulting from HIV-1 downregulating HLA-C on infected cells in some individuals but not others are unclear. Variation between HIV-1 viruses provides an opportunity to identify selection pressures in human individuals which may be relevant. In this study we have characterized HLA-C downregulation for a wide range of primary viruses. We demonstrate that HIV-1 viruses from the latent reservoir of certain individuals downregulate HLA-C, that different quasispecies members can vary widely in their ability to downregulate HLA-C during chronic infection, and that viral downregulation of HLA-C shows a striking adaptation to the HLA genotype of the host.