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

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-1specific 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.

Vaccinal effect of HIV-1 antibody therapy: dream or reality?

“…Similarly, CTLA-4 blocking agents also augment HIV-1 antibody responses, either alone or in combination with OX40 agonistic antibodies [74]. PD1 and TIGIT blockade have also been shown to enhance NK cell function [75,76]. Finally, the combination of different ICB (i.e., CTLA4, LAG-3, and TIGIT) might also be beneficial in improving anti-HIV immune response [77], although potential adverse effects of such a combination cannot be ruled out.…”

Negative Regulation and Protective Function of Natural Killer Cells in HIV Infection: Two Sides of a Coin

“…Expression of TIGIT, an inhibitory receptor and classical immune checkpoint, is elevated in chronic infectious diseases or tumors and related to NK cell dysfunction ( 34 , 35 ). Zhang et al.…”

“…Immunoreceptor Tyrosine-Based Inhibition Motif (ITIM) Domains (TIGIT) and DNAM-1(CD226) Expression of TIGIT, an inhibitory receptor and classical immune checkpoint, is elevated in chronic infectious diseases or tumors and related to NK cell dysfunction (34,35). Zhang et al found that an increase in the number of NK cells expressing TIGIT leads to higher HIV load, and TIGIT pos NK cells exhibit less-effective killing than TIGIT neg NK cells in HIV-infected individuals (36).…”

“…It is possible that TIGIT upregulation offsets the activation of CD226 on NK cells. Although TIGIT blockade enhances NK cell responses (35,38), Vendrame et al demonstrated that TIGIT blockade does not enhance NK cell-mediated killing of HIV-infected host cells, whereas TIGIT co-expression with multiple activation markers (CD2, 2B4, CD226, NTB-A) enhances the functional response of NK cells to tumors, cytokine activation, and virus-infected cells (40). Further studies of the function of TIGIT on NK cells during HIV infection are warranted.…”

Effective innate immune response in natural HIV-1 controllers. Can mimicking lead to novel preventive and cure strategies against HIV-1?

“…In addition, CD155 expression by T cells combined with NKG2D expression on NK cells has been described to increase cytotoxic capacities to eliminate HIV-infected cells in vitro [70]. On the other hand, blockade of the inhibitory checkpoint inhibitory receptor TIGIT on NK cells, which is the ligand of CD155, increases NK cell activity against HIV-1 infected CD4þ T cells in PWH in vitro [71].…”