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NOD2 and TLR8 Agonists Enhance IL-15 Mediated Activation of HIV Expression
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http://www.croiwebcasts.org/console/player/44913?mediaType=slideVideo&
CROI 2020
Reported by Jules Levin
Jasmine Kaur1, Jacob Lalezari2, Rebecca Hoh3, Steven Deeks3, Wade Blair1, Tomas Cihlar1, Jeffrey P.Murry1
1Gilead Sciences, Foster City, California, USA; 2Quest Clinical Research, San Francisco, California, USA; 3Department of Medicine, University of California, San Francisco, California, USA
Abstract
The latent HIV reservoir is a barrier to achieving an HIV cure. Individual reservoir-targeting agents have shown potential activity in exploratory clinical trials, but it is likely that activation of HIV expression would enhance and/or accelerate the depletion of the latent reservoir. We previously identified clinically advanced agents that modestly activate HIV expression in cells isolated from ART-suppressed people living with HIV (PLWHIV), including IL-15 and agonists of multiple pattern recognition receptors (PRRs), such as toll-like receptor (TLR) and Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) agonists. Here we identify combinations of agents that have greater activity than either agent alone.
Peripheral blood mononuclear cells (PBMCs) were isolated from ART-suppressed PLWHIV then treated with various PRR agonists individually or in combination with IL-15. Cytokine production and surface markers of T cell activation were assessed 24 hours after treatment initiation. HIV RNA in culture supernatants and T cell proliferation were quantified following a 4-day treatment with PRR agonists. Wilcoxon matched pair signed rank test and Bliss independence model were used for statistical and synergy analysis, respectively.
In PBMCs from 7 ART-suppressed PLWHIV, IL-15 alone induced a 3.9-fold increase in HIV expression relative to control, while NOD2 and TLR8 agonists induced 3.0- and 3.2-fold increases, respectively (geometric means, p < 0.05 for each). In combination with IL-15, NOD2 and TLR8 agonists had the greatest effect, increasing HIV expression 14- and 11-fold, respectively (p < 0.05 for both compared to IL-15 alone). This was not significantly different from that induced by PMA and ionomycin (18-fold). The combination of NOD2 and IL-15 showed the clearest synergy. Correspondingly, both NOD2 and TLR8 agonists increased the levels of cytokines and activation markers produced in response to IL-15 stimulation, but had minimal additional effect on CD4 T cell proliferation.
Combining either NOD2 or TLR8 agonist with IL-15 significantly increased HIV expression and, in cells from several donors, approached that observed with the mitogenic activation control. This identifies clinically tested agents capable of robustly inducing HIV. It is important to consider that these combinations can also activate broader immunity and potentially augment immune-mediated reservoir clearance.
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