Role of cytokine agonists and immune checkpoint inhibitors toward HIV remission

Abstract

Purpose of review: The current article describes the current status of the use of cytokines and immune-checkpoint inhibitors as therapeutic strategies toward HIV remission.

Recent findings: Clinical trials using IL-2 and IL-7 showed increased levels of circulating T cells, although no reduction to the viral reservoir was observed. Studies in nonhuman primates (NHP) demonstrated that experimental IL-15 administration increased proliferation and cytotoxicity of simian immunodeficiency virus (SIV)-specific CD8 T cells, and promoted their localization to the lymph node (LN) B cell follicles. Immune checkpoint modulators targeting programed cell death-1 and cytotoxic T-lymphocyte associated protein 4, successfully used in oncologic diseases, have shown potential to restore HIV-specific function in early stage clinical trials, while also transiently increasing plasma and cell-associated viral RNA. Due to the complexity of the mechanisms regulating HIV persistence, it is very likely that combinatorial approaches, including cytokines with immune checkpoint blockades (ICBs), will be needed to achieve HIV remission.

Summary: The present review covers approaches based on cytokine agonists and immune checkpoint inhibitors that have shown promise toward therapeutic pathways for HIV remission. These strategies have been tested preclinically in animal models of HIV infection to determine their safety, activity, and mechanisms of action, with the goal to inform the design of the most synergistic combinatorial strategies. Several of these interventions are included in ongoing or planned clinical trials in HIV infection; these trials will elucidate the clinical efficacy of these innovative immunotherapy approaches toward HIV remission.

Figure 1.

(A) Administration of IL-2 and IL-7 results in expansion and circulating CD4⁺ and CD8⁺ T cells, while also inducing transient production of viral RNA in the plasma. (B) Treatment with IL-15 and ALT-803 induces proliferation of Ag-specific CD8⁺ T cells and NK cells, and the Ag-specific CD8⁺ T cells then localize to the B cell follicle. (C) Administration of IL-21 results in decreased T cell activation, while at the same time maintaining T_H17 populations in the mucosal tissue. This results in maintenance of barrier integrity and a reduction to microbial translocation and systemic inflammation.

Figure 2.

(A) PD-1⁺ Memory CD4⁺ T cells have been described to be enriched in integrated HIV-DNA. Blockade of PD-1 with a PD-1-mAb results in transient reactivation of virus, while restoring HIV-specific CD8+ T cell function to (B) CTLA-4⁺ Memory CD4⁺ T cells have also been shown to be enriched for HIV-DNA and replication competent virus. Blockade of CTLA-4 with a CTLA-4-mAb results in reactivation of viral production.