Background
Elevated levels of IL-10 and PD1 contribute to HIV reservoir persistence, an impediment for HIV eradication. IL-10 contributes to the lack of effector function, antigen-presentation and promotes HIV reservoir survival. PD-1 expression is associated with T cell exhaustion and HIV latency. We hypothesized that the dual blockade of IL-10 and PD-1 could synergize and lead to viral rebound control post-ATI (Analytical Treatment Interruption) and to reduced SIV reservoir size
Methods
28 rhesus macaques (RMs) infected with SIVmac239 started antiretroviral therapy (ART) 42 days post-infection, maintained for 14-months. Rhesusized aIL-10 (n=10), aIL-10/aPD-1 (Combo therapy – n=10), or vehicle (n=8), infused every 3-weeks was administered starting 12 weeks pre-ATI and stopped 14-weeks post-ATI (week 26). Here, we utilized transcriptomic and metabolomic data from PBMCs and LNs to decipher the mechanisms of VL control observed in aPD1+aIL10 treated RMs.
Results
Week 12 (pre-ATI) PBMC and LN transcriptomic profiling of aPD1+aIL10 treated RMs revealed a significant enrichment of Bile Acid (BA) metabolism and synthesis characterized by elevated FXR levels and enhanced BA and BA salt synthesis. Concordantly, elevated metabolites (tauro-litho-cholate sulfate, litho-cholate sulfate) mapping to primary and secondary BA metabolism were elevated in dual-treated RMs. Additionally, enhanced levels of Type I IFN production characterized by innate anti-viral restriction factors RFs (IRF1, IRF7, APOBECs, TRIMs) were elevated in aPD1+aIL10 treated RMs. Notably, we observed a positive correlation between BA synthesis and Type I IFN RFs. Importantly, both mechanisms were negatively associated with the magnitudes of SIV RNA/DNA and 2LTR circles measured in LN.
Conclusions
Our data highlight that administration of combo therapy drives innate Type I IFN signaling characterized by an intact anti-viral response downstream of BA synthesis. Of note, we also observed several pathways mapping to FGF signaling which were negatively correlated with week 36 (post-ATI) virological outcomes. FGF15 and its human ortholog FGF19 are gut-derived circulating hormone that represses hepatic BA synthesis. Combo (aIL10+aPD1) treated RMs inhibit FGF signaling. Altogether, these data highlight the interplay between FGF signaling, BA synthesis/signaling and IFN signaling/antiviral immunity. These data also demonstrate that inhibition of FGF signaling could be used as an effective therapy.