Novel insights into immune checkpoints in HIV/SHIV infection: from SHIVSF162P3-infected elite controllers to therapeutic strategy

During chronic HIV-1 infection, the upregulation of immune checkpoints (ICs) on lymphocytes contributes to persistent immune dysfunction, T-cell exhaustion, and inadequate virological control, highlighting the potential role of ICs in HIV functional cure strategy. Despite extensive research on ICs, the expression dynamics and immunological impact of ICs in natural HIV/SHIV infection, particularly among antiretroviral therapy (ART)-free elite controllers (ECs), remain poorly understood. In this study, we monitored a cohort of SHIV(SF162P3)-infected rhesus macaques (RMs), identifying four ECs and four progressors (PGs) through longitudinal evaluation. We observed low-level expression of ICs in both peripheral blood and lymph nodes of ECs, characterized by a particularly pronounced restriction in the expression of TIGIT and BTLA. This attenuated IC profile correlated with enhanced T-cell functionality, reduced exhaustion markers, and reduced viral reservoirs in peripheral and lymphoid tissues. Transcriptomic profiling revealed that TIGIT is a critical checkpoint marker involved in multiple synergistic cofunctions related to HIV/SIV-specific immune regulation. Collectively, our findings establish a dual role for ICs in perpetuating T-cell exhaustion and viral reservoir persistence, paving the way for IC blockade in future HIV cure strategies.IMPORTANCERhesus macaques spontaneously controlling simian-human immunodeficiency virus (SHIV) without antiretroviral therapy have low-level expression of immune molecules (ICs), characterized by TIGIT and BTLA. These molecules are linked to enhanced immune function and reduced viral presence in peripheral blood and lymph nodes. Transcriptomic profiling revealed that TIGIT is a critical checkpoint marker involved in multiple synergistic cofunctions related to HIV/SIV-specific immune regulation in both humans and macaques. Blocking TIGIT improved polyfunctional T-cell responses, thereby offering a potential new treatment strategy and providing critical insights for developing a functional HIV cure.