Background:
IL10 and PD1 contribute to HIV reservoir persistence impeding HIV eradication. We hypothesized that the dual blockade of IL10 and PD1 could synergize and lead to SIV-functional cure by triggering intrinsic antiviral immunity in monocytes and CD4 T cells resulting in lack of viral re-seeding post-ATI (Analytical Treatment Interruption) and by boosting innate and adaptive cellular effector function.
Methods:
18 rhesus macaques (RMs) infected with SIVmac239 under antiretroviral therapy (ART) for 14 months started at 42 days post-infection received Rhesusized aIL10/aPD1 (Combo n=10) or vehicle (control n=8), administered every 3-weeks between 12 weeks pre-ATI and 14-weeks post-ATI. Animals were followed longitudinally for biospecimen collections.
Results:
Durable viral load control post-ATI (<1000 cps/mL in 9/10 animals) was observed in the combo treated RMs up to 6 months post-ATI (Fig 1). Post-ATI stable IPDA and 2LTR readouts was also observed in combo-treated animals as compared to the control group. Gene expression analysis revealed significantly elevated restriction factor machinery in the lymph nodes (LN) cells from the combo treated group pre-ATI (APOBECs, SAMDH, ISGs) that was persistent till the end of the follow up (6 months post-ATI). Monocytes, CD8 and CD4 T cells presented significantly higher protein-expression of pIRF3 and pIRF7. Use of multi-ome platform that allows simultaneous single cell assessment of transcription and epigenetic profiles showed that the enhanced expression of antiviral ISGs was concomitant with the increased chromatin accessibility of the IRF3, IRF7 and Stat1 transcription factors known to confer refractoriness to viral infections by inducing Interferon antiviral genes. Moreover, pre-ATI, the accessibility of the Tbet locus and its target genes such as granzyme B, perforin and IFNg, in CD4 and CD8 T cells from combo treated animals was observed. This poised antiviral environment was associated with viral rebound control.
Conclusions:
The combo therapy triggers an epigenetic reprogramming of innate and adaptive immune cells highlighted by poised intrinsic antiviral machinery and poised effector molecules of T cell function that together synergize to block the de novo CD4 T cell infection post-ATI and viral dissemination.
