CD155 on HIV-Infected Cells Is Not Modulated by HIV-1 Vpu and Nef but Synergizes with NKG2D Ligands to Trigger NK Cell Lysis of Autologous Primary HIV-Infected Cells

Davis, Zachary; Sowrirajan, Bharatwaj; Cogswell, Andrew; Ward, Jeffery P.; Planelles, Vicente; Barker, Edward

doi:10.1089/aid.2015.0375

Cited by 21 publications

(29 citation statements)

References 35 publications

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“…The lack of a benefit for TIGIT blockade may also be explained by the fact that TIGIT is simply not engaged during NK cell recognition of HIV-infected cells. We found that TIGIT ligands CD155 and CD112 are not upregulated on CD4 + T cells by HIV infection in vitro, consistent with previous reports [67][68][69]. We also found that TIGIT ligands were not upregulated in HIV + women, though this differs from the findings of Yin et al [48], who reported elevated CD155 expression on CD4 + T cells from HIV-infected individuals.…”

Section: Nk Cells Undergo Significant Changes During Chronic Hiv Infesupporting

confidence: 91%

TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

Vendrame

Seiler

Ranganath

et al. 2019

Preprint

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Objective: Our objective was to investigate the mechanisms that govern natural killer (NK) cell responses to HIV, with a focus on specific receptor-ligand interactions involved in HIV recognition by NK cells. Design and Methods: We first performed a mass cytometry-based screen of NK cell receptor expression patterns in healthy controls and HIV + individuals. We then focused mechanistic studies on the expression and function of T cell immunoreceptor with Ig and ITIM domains (TIGIT). Results: The mass cytometry screen revealed that TIGIT is upregulated on NK cells of untreated HIV + women, but not in antiretroviral-treated women. TIGIT is an inhibitory receptor that is thought to mark exhausted NK cells; however, blocking TIGIT did not improve anti-HIV NK cell responses. In fact, the TIGIT ligands CD112 and CD155 were not upregulated on CD4 + T cells in vitro or in vivo, providing an explanation for the lack of benefit from TIGIT blockade. TIGIT expression marked a unique subset of NK cells that express significantly higher levels of NK cell activating receptors (DNAM-1, NTB-A, 2B4, CD2) and exhibit a mature/adaptive phenotype (CD57 hi , NKG2C hi , LILRB1 hi , FcRγ lo , Syk lo ). Furthermore, TIGIT + NK cells had increased responses to mock-infected and HIV-infected autologous CD4 + T cells, and to PMA/ionomycin, cytokine stimulation and the K562 cancer cell line. Conclusions: TIGIT expression is increased on NK cells from untreated HIV + individuals. Although TIGIT does not participate directly in NK cell recognition of HIV, it marks a population of mature/adaptive NK cells with increased functional responses. Antibody conjugation, mass cytometry staining and data acquisitionAntibodies were conjugated using MaxPar® ×8 labeling kits (Fluidigm). To ensure antibody stability over time, antibody panels were lyophilized into single-use pellets prior to use (Biolyph). Cells were stained for mass cytometry as described previously [51,52] and resuspended in 1× EQ Beads (Fluidigm) before acquisition on a Helios mass cytometer (Fluidigm). In vitro HIV infectionReplication competent (Q23-FL) HIV-1 was made by transfection and titrated as described [51]. CD4 + T cells were activated for 2 days with plate-bound anti-CD3 (clone OKT3, eBioscience, 10 µg/ml), soluble anti-CD28/CD49d (clones L293/L25, BD Biosciences, 1 µg/ml each) and phytohemagglutinin (eBioscience, 2.5 µg/ml). CD4 + T cells were infected overnight with Q23-FL via ViroMag R/L magnetofection (Oz Biosciences) at a multiplicity of infection of 20. HIV infection was as measured by intracellular p24. TIGIT blockade assayCells were cultured in RPMI media containing 10% FBS (Thermo Fisher Scientific) and 1% penicillin/streptomycin/amphotericin (Thermo Fisher Scientific) (RP10). NK cells were incubated in 24-well plates at a concentration of 2x10 6 cells/ml in for 3 days at 37°C with 5% CO2, with addition of rhIL-2 (R&D Systems, 300 IU/ml). After 3 days, NK cells were washed with fresh media and plated in 96-well plates (80,000-100,000 cells/well). Blocking mIgG1κ anti-h...

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Section: Nk Cells Undergo Significant Changes During Chronic Hiv Infesupporting

confidence: 91%

TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

Vendrame

Seiler

Ranganath

et al. 2019

Preprint

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“…We analyzed by flow cytometry the expression of some ligands on target cells that either trigger NK activation or initiate inhibitory NK signaling by binding to NK inhibitory receptors. The activating ligands included NTB-A, which binds NTB-A on the NK cell surface and leads to activation and secretion of interferon-γ, CD48, which binds 2B4, ULBP-1 and -2, ligands that bind NKG2D and that have been demonstrated to be upregulated in the setting of HIV-1 infection by the viral protein vpr ( 32 ), and CD155, a NK ligand that binds DNAM-1 on NK cells and induces activation ( 33 ). The inhibitory included HLA-E and HLA-Bw4, NK ligands that initiate inhibitory NK signaling by binding to NK receptors NKG2A and KIR3DL1, respectively.…”

Section: Resultsmentioning

confidence: 99%

HIV Latency-Reversing Agents Have Diverse Effects on Natural Killer Cell Function

et al. 2016

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In an effort to clear persistent HIV infection and achieve a durable therapy-free remission of HIV disease, extensive pre-clinical studies and early pilot clinical trials are underway to develop and test agents that can reverse latent HIV infection and present viral antigen to the immune system for clearance. It is, therefore, critical to understand the impact of latency-reversing agents (LRAs) on the function of immune effectors needed to clear infected cells. We assessed the impact of LRAs on the function of natural killer (NK) cells, the main effector cells of the innate immune system. We studied the effects of three histone deacetylase inhibitors [SAHA or vorinostat (VOR), romidepsin, and panobinostat (PNB)] and two protein kinase C agonists [prostratin (PROST) and ingenol] on the antiviral activity, cytotoxicity, cytokine secretion, phenotype, and viability of primary NK cells. We found that ex vivo exposure to VOR had minimal impact on all parameters assessed, while PNB caused a decrease in NK cell viability, antiviral activity, and cytotoxicity. PROST caused non-specific NK cell activation and, interestingly, improved antiviral activity. Overall, we found that LRAs can alter the function and fate of NK cells, and these effects must be carefully considered as strategies are developed to clear persistent HIV infection.

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“…In contrast, reports on HIV-mediated regulation of the expression of other NKG2D ligands, i.e., MIC-A and MIC-B, on CD4 + T cells are conflicting [ 52 , 54 , 55 ]. HIV infection induces the loss of surface expression of CD155 on the Jurkat T cell line, however, this could not be reproduced in bulk p24 + primary HIV NL4-3 -infected T cells, which found CD155 to be modestly upregulated [ 56 , 57 , 58 ]. Infection of the human monocytic cell line U937 with primary isolates of an Indian HIV-1 subtype C induced the downregulation of CD80 and CD86 [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Expression Profiles of Ligands for Activating Natural Killer Cell Receptors on HIV Infected and Uninfected CD4+ T Cells

Tremblay‐McLean

Bruneau

Lebouché

et al. 2017

Viruses

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Natural Killer (NK) cell responses to HIV-infected CD4 T cells (iCD4) depend on the integration of signals received through inhibitory (iNKR) and activating NK receptors (aNKR). iCD4 activate NK cells to inhibit HIV replication. HIV infection-dependent changes in the human leukocyte antigen (HLA) ligands for iNKR on iCD4 are well documented. By contrast, less is known regarding the HIV infection related changes in ligands for aNKR on iCD4. We examined the aNKR ligand profiles HIV p24+ HIV iCD4s that maintained cell surface CD4 (iCD4+), did not maintain CD4 (iCD4−) and uninfected CD4 (unCD4) T cells for expression of unique long (UL)-16 binding proteins-1 (ULBP-1), ULBP-2/5/6, ULBP-3, major histocompatibility complex (MHC) class 1-related (MIC)-A, MIC-B, CD48, CD80, CD86, CD112, CD155, Intercellular adhesion molecule (ICAM)-1, ICAM-2, HLA-E, HLA-F, HLA-A2, HLA-C, and the ligands to NKp30, NKp44, NKp46, and killer immunoglobulin-like receptor 3DS1 (KIR3DS1) by flow cytometry on CD4 T cells from 17 HIV-1 seronegative donors activated and infected with HIV. iCD4+ cells had higher expression of aNKR ligands than did unCD4. However, the expression of aNKR ligands on iCD4 where CD4 was downregulated (iCD4−) was similar to (ULBP-1, ULBP-2/5/6, ULBP-3, MIC-A, CD48, CD80, CD86 and CD155) or significantly lower than (MIC-B, CD112 and ICAM-2) what was observed on unCD4. Thus, HIV infection can be associated with increased expression of aNKR ligands or either baseline or lower than baseline levels of aNKR ligands, concomitantly with the HIV-mediated downregulation of cell surface CD4 on infected cells.

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CD155 on HIV-Infected Cells Is Not Modulated by HIV-1 Vpu and Nef but Synergizes with NKG2D Ligands to Trigger NK Cell Lysis of Autologous Primary HIV-Infected Cells

Cited by 21 publications

References 35 publications

TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

TIGIT is upregulated by HIV-1 infection and marks a highly functional adaptive and mature subset of natural killer cells

HIV Latency-Reversing Agents Have Diverse Effects on Natural Killer Cell Function

Expression Profiles of Ligands for Activating Natural Killer Cell Receptors on HIV Infected and Uninfected CD4+ T Cells

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