Background:
Vesatolimod (VES) is a well tolerated and selective toll-like receptor-7 agonist under development as part of an HIV cure regimen. VES treatment increases interferon-stimulated gene (ISG) expression and immune cell activation in people with HIV (PWH); additionally, VES monotherapy promotes a modest delay in HIV rebound in HIV controllers, and VES pharmacodynamic response is higher with 8 mg compared with 10-12 mg doses in PWH treated during chronic infection. We used mRNA-Seq to further investigate the immune mechanism and regulation of type I interferon (IFN) signaling pathways in response to VES in a phase 1b, double-blind, placebo-controlled trial (NCT02858401; GS-US-382-1450).
Methods:
The study enrolled virally suppressed PWH (age ≥18 years, plasma HIV-1 RNA <50 copies/mL) and randomized 6:2 to receive VES or placebo biweekly for 10 doses. Whole blood mRNA collected pre-dose and 24 hours after doses 1 and 10 from participants who received VES 6 mg, 8 mg, or 10-12 mg (n=24) was used for mRNA-Seq (Illumina Stranded mRNA Prep; NovaSeq 6000). A linear mixed-effects and placebo-adjusted model was used to test for differentially expressed genes (DEGs) associated with type I IFN regulation and regulators of pattern recognition receptors (FDR<0.1).
Results:
VES consistently upregulated DEGs associated with type I IFN signaling after doses 1 and 10 in all 3 doses evaluated (Figure). After dose 1, the highest number of DEGs, including those associated with activation and inhibition, was observed with VES 8 mg (38 genes), followed by VES 6 mg (21 genes) and VES 10/12 mg (15 genes); type I IFN activation was most pronounced with VES 8 mg versus the other doses. After dose 10, VES 6 mg induced the highest type I IFN activation and numbers of genes (49), followed by VES 8 mg (31) and VES 10/12 mg (27), respectively. Also, a lower induction in type I IFN activation was observed by post dose 10 versus post dose 1 in all but the 6 mg dose group, with the greatest reduction in the 8 mg group. VES-mediated type I IFN activation was greatest after dose 1 at 8 mg, followed by dose 10 at 6 mg.
Conclusions:
Whole blood transcriptome analysis identified pronounced differences in gene expression based on VES dose and administration order. The results suggest that a cumulative effect of multiple VES doses could modulate VES pharmacodynamic response, which should be taken into account in future combination studies with VES.
