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TIGIT blockade enhances NK cell activity against autologous HIV‐1‐infected CD4+ T cells

ABSTRACT: Abstract

Objectives

During chronic human immunodeficiency virus (HIV)‐1 infection, inhibitory molecules upregulated on lymphocytes contribute to effector cell dysfunction and immune exhaustion. People living with HIV (PLWH) are at greater risk for age‐related morbidities, an issue magnified by human cytomegalovirus (CMV) coinfection. As CMV infection modifies natural killer (NK) cell properties and NK cells contribute to protection against HIV‐1 infection, we considered the role of T‐cell immunoreceptor with immunoglobulin and intracellular tyrosine inhibitory motif domains (TIGIT) in NK cell‐based HIV‐1 immunotherapy and elimination strategies.

Methods

We measured TIGIT expression on immune cell subsets of 95 PLWH and assessed its impact on NK cell function, including elimination of autologous CD4+ T cells infected through reactivation of endogenous HIV‐1.

Results

TIGIT was expressed on CD4+ T cells, CD8+ T cells and NK cells from PLWH. Although TIGIT levels on T cells correlated with HIV‐1 disease progression, the extent of TIGIT expression on NK cells more closely paralleled adaptation to CMV. TIGIT interacts with its predominant ligand, poliovirus receptor (PVR), to inhibit effector cell functions. Circulating CD4+ T cells from PLWH more frequently expressed PVR than HIV‐seronegative controls, and PVR expression was enriched in CD4+ T cells replicating HIV‐1 ex vivo. Treatment with anti‐TIGIT monoclonal antibodies increased NK cell HIV‐1‐specific antibody‐dependent cytotoxicity in vitro and ex vivo.

Conclusion

Blocking TIGIT may be an effective strategy to invigorate antibody‐dependent NK cell activity against HIV‐1 activated in cellular reservoirs for cure or treatment strategies. In this study, we found positive correlations between the frequency of TIGIT expression on natural killer (NK) cells from people living with human immunodeficiency virus (HIV)‐1 and markers of NK cell adaptation to cytomegalovirus infection. The main ligand for TIGIT, poliovirus receptor (PVR), was expressed on circulating CD4+ T cells of people living with HIV‐1 and its expression increased with ex vivo reactivation of HIV‐1 replication. Preventing NK cell TIGIT interaction with PVR augments NK cell effector functions against autologous HIV‐1 infected CD4+ T cells.

SUBMITTER: Holder K

PROVIDER: S-EPMC8527024 | biostudies-literature |

REPOSITORIES: biostudies-literature

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