In Vivo Activation of Human NK Cells by Treatment with an Interleukin-15 Superagonist Potently Inhibits Acute In Vivo HIV-1 Infection in Humanized Mice

Abstract

T he crucial role of the human immunodeficiency virus (HIV)-specific T cell and antibody response mounted by the adaptive immune system to control HIV-1 infection is well established (1). However, during acute infection, viremia is not controlled because it takes several weeks after the initiation of infection for the adaptive immune response to activate and clonally expand sufficient numbers of HIV-1-specific T cells and B cells to suppress HIV-1 infection (2). This delay in the mobilization of the adaptive immune response permits HIV-1 to rapidly replicate and disseminate during the acute phase of infection, leading to the production of high plasma viral loads, which are associated with an adverse disease course (3,4). Early control of HIV-1 replication can have a beneficial impact on the subsequent disease course, as evidenced by the ability of some individuals whose viremia was suppressed by combination antiretroviral therapy (cART) during acute infection to achieve long-term infection control despite lacking protective HLA-B alleles (5-7). Prior to the development of an effective HIV-1-specific adaptive immune response, natural killer (NK) cells, crucial innate immune effector cells which are

Trans-presentation of interleukin-15 by interleukin-15 receptor alpha is dispensable for the pathogenesis of autoimmune type 1 diabetes

“…6,25,26 Therefore, it is possible that IL-15 presents in the circulation of NOD.scid.Il15ra -/-recipients can bind to IL-15Ra present on donor cells and trans-present IL-15 to autoreactive effector CD8 1 T cells. To address the role of donor-derived IL15Ra, we adoptively transferred splenocytes from diabetic NOD.…”

The human IL-15 superagonist ALT-803 directs SIV-specific CD8+ T cells into B-cell follicles

“…Coupled with recent data that ALT-803 reverses viral latency in vitro, 17 it could potentially mediate both the "shock" and the "kill" in eradication strategies. Finally, given that ALT-803 also potently activates NK cells and increases their cytolytic potential, 14,16 it could also be combined with broadly neutralizing antibodies to mobilize both cytotoxic CD8 1 T-cell-and NK-mediated antibody-dependent cell-mediated cytotoxicity to clear latent virus. Cumulatively, these 3 effects suggest that ALT-803 is a formidable addition to the HIV eradication armament.…”

“…8,9,14,15 These findings have recently been extended to HIV infection, where ALT-803-activated NK cells inhibit acute HIV infection in vivo, 16 and ALT-803 also reactivates latent virus in vitro. 17 In this study, we demonstrated that ALT-803 significantly enhanced lymphocyte proliferation and activation, specifically CD16…”

HIV-specific CD8+ T cells and HIV eradication

“…As an alternative or adjunct to blocking inhibitory pathways, CD8 + T cell function can be enhanced by the provision of cytokines or other immunostimulatory agents. IL-15 agonists are of particular interest in this regard, having been shown to enhance CD8 + T cell and NK cell activity in a number of preclinical models (135)(136)(137)(138)(139), and the IL-15 superagonist ALT-803 is moving into a clinical trial in cART-treated HIV-infected subjects (ClinicalTrials.gov identifier: NCT02191098). Other immunostimulatory agents include TLR-2 agonists, which reverse CD8 + T cell exhaustion and enhance both tumor-and pathogen-specific T cell responses in vivo (140)(141)(142), and agonistic Abs against 41BB or CD40 (143-145), among others.…”