TIGIT Marks Exhausted T Cells, Correlates with Disease Progression, and Serves as a Target for Immune Restoration in HIV and SIV Infection

Abstract

HIV infection induces phenotypic and functional changes to CD8 ⁺ T cells defined by the coordinated upregulation of a series of negative checkpoint receptors that eventually result in T cell exhaustion and failure to control viral replication. We report that effector CD8 ⁺ T cells during HIV infection in blood and SIV infection in lymphoid tissue exhibit higher levels of the negative checkpoint receptor TIGIT. Increased frequencies of TIGIT ⁺ and TIGIT ⁺ PD-1 ⁺ CD8 ⁺ T cells correlated with parameters of HIV and SIV disease progression. TIGIT remained elevated despite viral suppression in those with either pharmacological antiretroviral control or immunologically in elite controllers. HIV and SIV-specific CD8 ⁺ T cells were dysfunctional and expressed high levels of TIGIT and PD-1. Ex-vivo single or combinational antibody blockade of TIGIT and/or PD-L1 restored viral-specific CD8 ⁺ T cell effector responses. The frequency of TIGIT ⁺ CD4 ⁺ T cells correlated with the CD4 ⁺ T cell total HIV DNA. These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells and suggest TIGIT along with other checkpoint receptors may be novel curative HIV targets to reverse T cell exhaustion.

Author Summary

HIV-1 infection contributes substantially to global morbidity and mortality, with no immediate promise of an effective vaccine. One major obstacle to vaccine development and therapy is to understand why HIV-1 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-1 specific target cells, they are unable to effectively keep up with rapid and dynamic viral replication in an individual. We have identified a novel combination pathway that can be targeted, TIGIT and PD-L1which 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-L1 pathway, we can reverse the defects of these viral specific immune cells. Our findings will give new directions to vaccines and therapies that will potentially reverse these dysfunctional cells and allow them to control HIV-1 replication, but also serve in “Shock and Kill” HIV curative strategies.