Immune Checkpoint Modulation and Reservoir Persistence in People Living with HIV

Taliikwa Nicholas Ceaser

Department of Pharmacognosy Kampala International University Uganda

Email:ceaser.taliikwa@studwc.kiu.ac.ug

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.

Keywords: Immune checkpoints, HIV reservoir, Latency reversal, T cell exhaustion, Antiretroviral therapy.

CITE AS: Taliikwa Nicholas Ceaser (2026). Immune Checkpoint Modulation and Reservoir Persistence in People Living with HIV. RESEARCH INVENTION JOURNAL OF SCIENTIFIC AND EXPERIMENTAL SCIENCES 6(1):1-7. https://doi.org/10.59298/RIJSES/2026/611700