Role of the TIGIT Immune Checkpoint Pathway in the Eradication of HIV Infection.

Abstract

HIV infection contributes substantially to global morbidity and mortality, with no immediate promise of an effective vaccine or cure. One major obstacle to vaccine development and therapy is to understand why HIV replication persists in a person despite the presence of viral specific immune responses. The emerging consensus has been that these immune cells are functionally ‘exhausted’ or anergic, and thus, although they can recognize HIV infected cells, they are unable to effectively keep up with rapid and dynamic viral replication in an individual. Negative checkpoint receptors (NCRs) are associated with immune dysfunction during chronic HIV infection. The goal of this study is to characterize an emerging NCR, TIGIT, in the context of HIV infection. The overall hypothesis is that TIGIT will be increased during HIV infection and limit anti-HIV responses, targeting the TIGIT pathway will reinvigorate existing anti-HIV T cell effector functions. Thus, these studies were conducted to elucidate the role of TIGIT in progressive HIV infection. We have identified a combination of NCR pathways that can be targeted, TIGIT and PD-1 that may be responsible, at least in part, for making these immune cells dysfunctional and exhausted and thus unable to control the virus. We show that by blocking the TIGIT and PD-1 pathway, we can reverse the defects of these viral-specific CD8 T cells. Furthermore, we extend our findings to the clinically relevant nonhnuman primate model of HIV/AIDS. In addition, we identify potential predictors of immune reinvigoration from clinically obtainable samples. Our findings will give new directions to vaccines and therapies that will potentially reverse these dysfunctional cells and allow them to control HIV replication, but also serve in enhanced “shock and kill” HIV curative strategies.