Abstract
Despite the success of antiretroviral therapy (ART) to halt viral replication and slow disease progression, this treatment is not curative and there remains an urgent need to develop approaches to clear the latent HIV reservoir. The human IL-15 superagonist N-803 (formerly ALT-803) is a promising anti-cancer biologic with potent immunostimulatory properties that has been extended into the field of HIV as a potential “shock and kill” therapeutic for HIV cure. However, the ability of N-803 to reactivate latent virus and modulate anti-viral immunity in vivo under the cover of ART remains undefined. Here, we show that in ART-suppressed, simian-human immunodeficiency virus (SHIV)SF162P3-infected rhesus macaques, subcutaneous administration of N-803 activates and mobilizes both NK cells and SHIV-specific CD8+ T cells from the peripheral blood to lymph node B cell follicles, a sanctuary site for latent virus that normally excludes such effector cells. We observed minimal activation of memory CD4+ T cells and no increase in viral RNA content in lymph node resident CD4+ T cells post N-803 administration. Accordingly, we found no difference in the number or magnitude of plasma viremia timepoints between treated and untreated animals during the N-803 administration period, and no difference in the size of the viral DNA cell-associated reservoir post N-803 treatment. These results substantiate N-803 as a potent immunotherapeutic candidate capable of activating and directing effector CD8+ T and NK cells to the B cell follicle during full ART suppression, and suggest N-803 must be paired with a bona fide latency reversing agent in vivo to facilitate immune-mediated modulation of the latent viral reservoir.
Highlights
The inability of antiretroviral therapy (ART) to clear the latent HIV reservoir, paired with the difficulties of life-long ART adherence, have shifted the focus of HIV research towards the development of therapies able to achieve a functional cure, namely ART-free remission from HIV
To explore the applicability of the clinical grade IL-15 superagonist N-803 to HIV cure strategies we tested the impact of N-803 on host immunity and latent virus in simian-human immunodeficiency virus (SHIV)-infected rhesus macaques
Our results suggest that N-803 beneficially modulates effector NK and CD8+ T cells by expanding the numbers of these cells and redistributing them to lymph node B cell follicles, a site known to harbor persistent latent virus during ART
Summary
The inability of antiretroviral therapy (ART) to clear the latent HIV reservoir, paired with the difficulties of life-long ART adherence, have shifted the focus of HIV research towards the development of therapies able to achieve a functional cure, namely ART-free remission from HIV. Over a decade after his transplant and discontinuation of ART, Timothy Brown shows no signs of HIV and continues to demonstrate that durable ART-free remission is an attainable goal [2]. HIV research has expanded its scope to include a wide variety of curative strategies including the most studied approach, “shock and kill” therapies [4]. These therapies function on the hypothesis that latency-reversing agents (LRAs) activate and flush out latent HIV for subsequent recognition and clearance by effector NK and CD8+ T cells. Several immune-based therapies are candidates to combat latent HIV and among these are the common γ-chain cytokines due to their capacity for robust T cell activation
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