Abstract

Human immunodeficiency virus (HIV) persisted in latent reservoirs despite effective antiretroviral therapy (ART), 
presenting the primary barrier to achieving a functional cure. Immune checkpoint inhibitors (ICIs), originally 
developed for cancer immunotherapy, have emerged as promising agents for reversing HIV latency by modulating 
T-cell exhaustion pathways. This narrative review critically synthesized current evidence on the therapeutic 
potential and challenges of ICIs in targeting HIV reservoirs. A comprehensive literature search was conducted 
across PubMed, Embase, and Web of Science databases (2015–2024) using keywords related to immune checkpoint 
inhibitors, HIV latency, viral reservoirs, and T-cell exhaustion. Principal findings indicated that programmed cell 
death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade can enhance HIV
specific immune responses and induce viral reactivation in vitro and in animal models. However, clinical trials in 
people living with HIV (PLWH) have demonstrated modest effects on reservoir reduction, with significant inter
individual variability and potential immune-related adverse events. Combination approaches integrating ICIs with 
latency-reversing agents and therapeutic vaccines showed promise but required optimization. The review concludes 
that while ICIs represent a rational therapeutic strategy for HIV reservoir elimination, substantial challenges remain 
in achieving clinically meaningful reservoir depletion. Enhanced understanding of checkpoint molecule dynamics, 
personalized treatment algorithms, and novel combination regimens are essential for translating this approach into 
effective cure strategies.