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Proteomic evidence of vesatolimod-induced enhancement of 'cross-talk' between innate and adaptive immune cells in HIV controllers on ART

Title
Proteomic evidence of vesatolimod-induced enhancement of 'cross-talk' between innate and adaptive immune cells in HIV controllers on ART
Presenter
Yanhui Cai
Authors
Y. Cai * (1), S.G. Deeks (2), C. Brinson (3), M. Ramgopal (4), N. Jones (2), E. DeJesus (5), A. Mills (6), P. Shalit (7), B. Moldt (1), L. Zhang (1), E. Vendrame (1), D.M. Brainard (1), D. SenGupta (1), O. Podlaha (1), J.J. Wallin (1)
Institutions
(1) Gilead Sciences Inc., Foster City, United States, (2) University of California, San Francisco, San Francisco, United States, (3) Central Texas Clinical Research, Austin, United States, (4) Midway Specialty Care Center, Fort Pierce, United States, (5) Orlando Immunology Center, Orlando, United States, (6) Southern California Men''s Medical Group, Los Angeles, United States, (7) Peter Shalit MD And Associates, Seattle, United States

BACKGROUND: Vesatolimod (VES), an oral TLR7 agonist, induces interferon-stimulated genes and circulating cytokines in a dose-dependent manner in healthy volunteers and PWH on ART. In a Phase 1b trial of VES in HIV controllers, we observed modest but significant delay in viral rebound and decrease in viral set-point, following ART interruption. We investigate mechanisms associated with these outcomes by assessing proteomic changes following VES.
METHODS: We enrolled 25 HIV controllers (pre-ART viral load 50-5000c/mL) on ART for '¥6mo. Seventeen participants received 10 biweekly doses of VES and 8 received placebo, followed by analytical treatment interruption. Immune cell activation after VES was evaluated using flow cytometry. Plasma samples were used for high-throughput proteomic analysis with Proximity Extension Assay (PEA) technology. Data were analyzed with Ingenuity Pathway Analysis.
RESULTS: Compared to placebo, VES cumulatively induced innate and adaptive immune cell activation. Geometric mean fluorescent intensity of CD40 on pDC, and frequency of CD69+CD56dim, CD69+CD56bright NK cells, and Ki67+CD4+ T cells were significantly increased 1-day after VES dose-10 (p=0.0007,p=0.0115,p=0.0311,p=0.0033). Frequency of activated monocytes (CD14+CD16+) and CD8+ T cells (CD38+CD8+) were increased by day-3 after VES dose-10 (p=0.0056;p<0.0001). Among 92 proteins evaluated by PEA, 21 proteins were significantly upregulated 1-day after VES dose-1 and 10 (p-value<0.05). Pathway analysis of shifts revealed significant increase in immune responses following VES treatment, including pathways involved in T-cell differentiation, recruitment, and migration (z-score'¥1.96) and in crosstalk between dendritic cells and NK cells, NK-cell signaling, Th1 pathways, and antiviral responses (z-score'¥1.96; Fig).


CONCLUSIONS: We utilized novel high-throughput proteomic analysis approach to explore mechanisms associated with VES outcomes. An unbiased model revealed extensive shifts in immune function after administration of VES, with evidence of 'cross-talk' between innate and adaptive immune response. Findings support the hypothesis that achievement of post-ART control requires combination of increased cellular immune responses coupled with balanced inflammatory response.