HIV-1 Vpu Mediates HLA-C Downregulation

Apps, Richard; Prete, Gregory Q. Del; Chatterjee, Pramita; Lara, Abigail; Brumme, Zabrina L.; Brockman, Mark A.; Neil, Stuart J. D.; Pickering, Suzanne; Schneider, Douglas K.; Piechocka-Trocha, Alicja; Walker, Bruce D.; Thomas, Rasmi; Shaw, George M.; Hahn, Beatrice H.; Keele, Brandon F.; Lifson, Jeffrey D.; Carrington, Mary

doi:10.1016/j.chom.2016.04.005

Cited by 125 publications

(170 citation statements)

References 71 publications

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“…This raises the possibility that cells infected with viruses encoding wild-type Nef are protected from NK cell-mediated ADCC by their incapacity to ligate sufficient activating receptors and capacity to ligate sufficient inhibitory NK cell receptors to generate a cumulative inhibitory NK cell signal. Indeed, previous research has demonstrated that HIV-1-infected targets express sufficient HLA-C and HLA-E to inhibit anti-HIV-1 ADCC (14,15) despite the ability of primary Vpu to downregulate HLA-C to various extents (38). Given that cumulative signals are important determinants of ADCC susceptibility, future research should assess if target cells infected with viruses coding for wild-type Nef become susceptible to ADCC after blockade of inhibitory NK cell receptors.…”

Section: Discussionmentioning

confidence: 99%

Impaired Downregulation of NKG2D Ligands by Nef Proteins from Elite Controllers Sensitizes HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity

Alsahafi

Richard

Prévost

et al. 2017

J Virol

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HIV-1 Nef clones isolated from a rare subset of HIV-1-infected elite controllers (EC), with the ability to suppress viral load to undetectable levels in the absence of antiretroviral therapy, are unable to fully downregulate CD4 from the plasma membrane of CD4 ϩ T cells. Residual CD4 left at the plasma membrane allows Env-CD4 interaction, which leads to increased exposure of Env CD4-induced epitopes and increases susceptibility of infected cells to antibody-dependent cellular cytotoxicity (ADCC). ADCC is mediated largely by natural killer (NK) cells, which control their activation status through the cumulative signals received through activating and inhibitory receptors. Recently, the activating NKG2D receptor was demonstrated to positively influence ADCC responses. Since HIV-1 Nef has been reported to reduce the expression of NKG2D ligands, we evaluated the relative abilities of Nef from EC and progressors to downmodulate NKG2D ligands. Furthermore, we assessed the impact of EC and progressor Nef on the ADCC susceptibility of HIV-1-infected cells. We observed a significantly increased expression of NKG2D ligands on cells infected with viruses coding for Nef from EC. Importantly, NKG2D ligand expression levels correlated with enhanced susceptibility of HIV-1-infected cells to ADCC. The biological significance of this correlation was corroborated by the demonstration that antibody-mediated blockade of NKG2D significantly reduced ADCC of cells infected with viruses carrying Nef from EC. These results suggest the involvement of NKG2D-NKG2D ligand interactions in the enhanced susceptibility of EC HIV-1-infected cells to ADCC responses.IMPORTANCE Attenuated Nef functions have been reported in HIV-1 isolated from EC. The inability of elite controller Nef to fully remove CD4 from the surface of infected cells enhanced their susceptibility to elimination by ADCC. We now show that downregulation of NKG2D ligands by HIV-1 Nef from EC is inefficient and leaves infected cells susceptible to ADCC. These data suggest a critical role for NKG2D ligands in anti-HIV-1 ADCC responses.KEYWORDS HIV-1, Nef, elite controllers, ADCC, NKG2D, gp120, CD4

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Section: Discussionmentioning

confidence: 99%

Impaired Downregulation of NKG2D Ligands by Nef Proteins from Elite Controllers Sensitizes HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity

Alsahafi

Richard

Prévost

et al. 2017

J Virol

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“…HIV ‐1 down‐regulates HLA class I expression on the surface of infected CD 4 + T cells so as to evade CD 8 + T‐cell lysis 86, 87. However, this action exposes the infected cells to recognition and lysis by natural killer ( NK ) cells through KIR s. The effectiveness of an NK cell response, and consequently the outcome of infection, are linked to the host's KIR genes, their copy number and the expression levels of their ligands.…”

Section: Kir Geneticsmentioning

confidence: 99%

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

et al. 2016

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SummaryKiller‐cell immunoglobulin‐like receptors (KIRs) are components of two fundamental biological systems essential for human health and survival. First, they contribute to host immune responses, both innate and adaptive, through their expression by natural killer cells and T cells. Second, KIR play a key role in regulating placentation, and hence reproductive success. Analogous to the diversity of their human leucocyte antigen class I ligands, KIR are extremely polymorphic. In this review, we describe recent developments, fuelled by methodological advances, that are helping to decipher the KIR system in terms of haplotypes, polymorphisms, expression patterns and their ligand interactions. These developments are delivering deeper insight into the relevance of KIR in immune system function, evolution and disease.

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“…Unlike HLA-A and HLA-B alleles, the surface expression level of HLA-C alleles is not down-regulated by Nef and therefore HLA-C may be relatively stable after HIV-1 infection (Cohen et al, 1999; Le Gall et al, 1998). However, a recent study demonstrated that some HIV strains are able to down-modulate HLA-C on the infected cell surface by Vpu (Apps et al, 2016). Thus, binding between peptide-HLA-C complex and KIR2D, which is sensitive to sequence variation of the bound peptide, might be key in regulating the activity of NK cells (Alter et al, 2011; Fadda et al, 2012; Thananchai et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Control by NK Cells via Reduced Interaction between KIR2DL2 and HLA-C∗12:02/C∗14:03

et al. 2016

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SUMMARY Natural killer (NK) cells control viral infection in part through the interaction between killer cell immunoglobulin-like receptors (KIRs) and their HLA ligands. We investigated 504 ART-free Japanese patients chronically infected with HIV-1 and identified two KIR/HLA combinations, KIR2DL2/HLA-C*12:02 and KIR2DL2/HLA-C*14:03, that impact suppression of HIV-1 replication. KIR2DL2+ NK cells suppressed viral replication in HLA-C*14:03+ or HLA-C*12:02+ cells to a significantly greater extent than did KIR2DL2− NK cells in vitro. Functional analysis showed that the binding between HIV-1-derived peptide and HLA-C*14:03 or HLA-C*12:02 influenced KIR2DL2+NK cell activity through reduced expression of the peptide-HLA (pHLA) complex on the cell surface (i.e. reduced KIR2DL2 ligand expression), rather than through reduced binding affinity of KIR2DL2 to the respective pHLA complexes. Thus, KIR2DL2/HLA-C*12:02 and KIR2DL2/HLA-C*14:03 compound genotypes have protective effects on control of HIV-1 through a mechanism involving KIR2DL2-mediated NK cell recognition of virus-infected cells, providing additional understanding of NK cells in HIV-1 infection.

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HIV-1 Vpu Mediates HLA-C Downregulation

Cited by 125 publications

References 71 publications

Impaired Downregulation of NKG2D Ligands by Nef Proteins from Elite Controllers Sensitizes HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity

Impaired Downregulation of NKG2D Ligands by Nef Proteins from Elite Controllers Sensitizes HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

HIV-1 Control by NK Cells via Reduced Interaction between KIR2DL2 and HLA-C∗12:02/C∗14:03

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