TIGIT engagement impairs antiviral effector functions of CD8⁺ T cells from people living with HIV

A persistent latent reservoir in long-lived CD4⁺ T-cells is the main obstacle to eradicating HIV-1 infection. Chronic HIV-1 infection functionally alters CD8⁺ T cells through upregulation of immune checkpoint receptors (ICs) such as T cell immunoreceptor with Ig and ITIM domains (TIGIT). Expression of ICs can result in impaired cytolytic activity and failure to suppress viral replication. Therefore, blocking IC receptors could be an adjunct therapeutic approach targeting the HIV reservoir in eradication strategies. This study employed TIGIT engagement and blockade on CD8⁺ T cells from people living with HIV(PLWH) to test how TIGIT expression affects T cell function. We tested TIGIT engagement on CD8⁺ T cells from PLWH in non-specific redirected cytotoxicity assays and tested the impact of TIGIT blockade on HIV antigen-specific CD8⁺ T cells. For PLWH with circulating CD8⁺ T cell cytotoxicity >10% in redirected killing assays, TIGIT engagement reduced cytotoxicity in 8/14 cases, showing that TIGIT engagement impairs killing by CD8⁺ T cells from some PLWH. About 20% of subjects tested by ELISpot had strong interferon-gamma (IFN)-γ responses against HIV Gag and/or Nef peptides (>1000 spot-forming units/106 peripheral blood mononuclear cells). Stimulation of HIV-specific CD8⁺ T cells with peptides in the presence of TIGIT-blocking mAb increased CD8⁺ T cell degranulation and IFN-γ production in certain individuals. Thus, generalized and HIV specific effector functions of CD8⁺ T cells from a subset of PLWH are inhibited by TIGIT expression. These data show that TIGIT blockade can improve antiviral effector cell function in certain PLWH. Identifying features of the subset of responsive CD8⁺ T cells will help direct blockade therapy to those PLWH most likely to benefit.