γc-cytokines in HIV Cure Research

Well tolerated, scalable strategies capable of targeting latent HIV reservoirs are essential for the development of cure approaches that can be implemented globally. In recent years, common γ-chain cytokines (γc-cytokines) have emerged as promising candidates as standalone interventions or in combination with complementary therapeutic strategies. γc-cytokines exhibit latency-reversing activity and immunomodulatory effects. In this review, we summarize recent in-vitro, ex-vivo, and in-vivo studies evaluating the use of γc-cytokines in HIV cure research.

γc-cytokines, particularly IL-2 and IL-15 (or the superagonist N-803), promote reactivation of latent HIV proviruses, especially when combined with approaches that enhance STAT-dependent transcriptional activity. Recent in-vivo studies demonstrate that IL-15-based therapies can contribute to viral control when administered with broadly neutralizing antibodies. In addition, IL-15/N-803, alone or in combination with other interventions, consistently enhance HIV-specific immune responses by boosting the survival, proliferation, and effector function of NK cells and CD8- T cells.

Collectively, γc-cytokines show promise as dual-function agents capable of targeting latent HIV reservoirs through latency reversal and immune enhancement. Emerging preclinical and clinical data support their integration into multipronged strategies aimed at reservoir reduction and sustained immune-mediated control of HIV, laying groundwork for the development of durable functional cure approaches.