Abstract

Despite effective antiretroviral therapy, people living with HIV harbored a latent viral reservoir in long-lived 
memory CD4+ T cells that prevents cure. Immune checkpoint molecules, initially recognized for their role in 
maintaining peripheral tolerance and preventing autoimmunity, have emerged as critical regulators of T cell 
exhaustion and viral persistence in chronic HIV infection. This review examined the bidirectional relationship 
between immune checkpoint expression and HIV reservoir dynamics, evaluating how checkpoint pathways 
contributed to reservoir establishment, maintenance, and potential therapeutic targeting. A comprehensive analysis 
of literature published between 2015 and 2024 was conducted, focusing on studies investigating checkpoint molecule 
expression, reservoir quantification, and experimental interventions in people living with HIV. Programmed cell 
death protein 1 (PD-1), cytotoxic T lymphocyte associated protein 4 (CTLA-4), T cell immunoglobulin and mucin 
domain containing protein 3 (TIM-3), and lymphocyte activation gene 3 (LAG-3) are preferentially expressed on 
HIV-infected cells and correlate with reservoir size. Checkpoint blockade enhanced HIV-specific immune responses 
in vitro and animal models, yet clinical trials have shown limited reservoir reduction despite immune activation. The 
reservoir persists in checkpoint-high memory subsets that exhibit metabolic quiescence and epigenetic modifications 
favoring latency. Combination approaches targeting multiple checkpoints alongside latency reversal agents 
demonstrate enhanced viral reactivation but raise safety concerns. Immune checkpoint modulation represented a 
promising but complex strategy for HIV reservoir elimination, requiring careful consideration of tissue 
compartmentalization, immune reconstitution potential, and the balance between viral reactivation and immune
mediated clearance.