Heterodimeric IL-15 disrupts follicular viral sanctuaries in lymph nodes and reduces SHIV RNA in macaques

Authors

• S Devasundaram
• A Valentin
• DC Watson
• E Moysi
• C Bergamaschi
• SP Fortis
• C Deleage
• JD Estes
• E Chertova
• JD Lifson
• C Petrovas
• BK Felber
• GN Pavlakis

Abstract

Background – HIV-infected follicular helper T cells (Tfh) are located in the B cell areas (follicles) of secondary lymphoid tissue, a location where CTL are typically excluded creating creating viral sanctuaries and long-term reservoirs for chronically infected CD4+ T cells. To disrupt these viral sanctuaries, therapeutic interventions that enhance the entry of cytotoxic CD8+ lymphocytes and natural killer (NK) cells into the follicles are needed. Heterodimeric interleukin-15 (hetIL-15) activates and expands cytotoxic T and NK cells. We study the effects of hetIL-15 alone or in combinations with anti-retroviral therapy (ART) and therapeutic vaccination in infected macaques to evaluate its use in the functional cure of HIV infection. Methods: Rhesus macaques, chronically infected by either SIV, SHIV or uninfected received injections of hetIL-15 over 2-8 weeks using increasing doses (step-dosing). Optimal dosing allowed high doses in the absence of adverse effects. Use of native macaque hetIL-15 allowed prolonged treatment without the development of anti-drug antibody. For SIV infected animals, ART treatment and therapeutic vaccination were combined with hetIL-15 to optimize virus control. Animals were studied for virus load and hetIL-15 effects over time on different lymphocyte populations by multi-parametric flow cytometry and quantitative multiplexed confocal microscopy (histo-cytometry). Cell-associated viral RNA and plasma viral load were measured by quantitative PCR. Results: hetIL-15 treatment was safe and well tolerated in macaques and resulted in a systemic expansion of CD8+ T lymphocytes and NK cells with higher granzyme B content. These expanded cell populations were found in both effector sites, such as liver, vagina and rectum, and secondary lymphoid tissues. Importantly, a significant increase in cytotoxic effector memory CD8+ T cells was found in lymph nodes (LN). CM9 tetramer staining demonstrated that the increase of CD8+ effector T cells in lymphoid organs included actively proliferating SIV-specific T cells with higher granzyme content. Imaging analysis by histo-cytometry revealed that effector CD8+ T cells infiltrated B cell follicles, where chronically infected follicular helper CD4+ T cells are located. Ex vivo experiments with CD8+ T cells recovered before and after hetIL-15 treatment demonstrated that memory CD8+ T cells had increased effector functions (cytokine production, degranulation and specific killing of target cells) after hetIL-15 treatment. Cell-associated viral RNA in LN and plasma viral load were both decreased following hetIL-15 treatment. Conclusions: Our results suggest that hetIL-15 could be useful in disrupting sanctuary sites within the B cell follicles and reducing long-term viral reservoirs in HIV-1 infected individuals, thus contributing to a functional cure of the infection.

Scientific Focus Area: Immunology

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