Background: Approaches to deplete the reservoir of HIV infection are needed. We investigated the impact of the combination of the latency reversing agent vorinostat (VOR) and AGS-004, an autologous dendritic cell immunotherapeutic, on the HIV reservoir.
Methods: 13 HIV+ individuals stably suppressed on antiretroviral therapy were screened for increased resting CD4+ T cell-associated HIV RNA (rca-RNA) after VOR exposure in vitro, and then after VOR dosing in vivo. AGS-004 was produced for 5 VOR responders using autologous dendritic cells co-electroporated with RNA expressing autologous HIV antigens and CD40 ligand. AGS-004 was administered every 3 weeks for 4 doses, followed by 10 oral doses of VOR 400 mg every 72 hours. Participants repeated the cycle of AGS-004 and VOR following a rest period. VOR exposure was validated by measuring expression of HDACi-responsive genes in vivo. HIV-specific T cell responses were measured by multiparameter flow cytometry and ELISPOT assays. Low-level HIV viremia was measured bya single-copy assay (SCA). rca-RNA and the frequency of resting CD4+
T-cell infection (RCI) was measured by quantitative viral outgrowth assay at baseline and after each cycle.
Results: No serious treatment-related adverse events were observed. HDACi responsive genes increased (HF10 and IRGM) or decreased (PHF15, PRM10) with VOR dosing. rcaRNA decreased significantly two (VV01 and VV02) participants, and a significant decrease in SCA was observed in VV02. However, unlike other cohorts dosed with AGS-004 HIV-specific T cell responses to the AGS-004 antigen payload increased only in VV02. And no uniform increase was seen in ex vivo ELISPOT to AGS-004-delivered antigens. Finally, there was no reproducible decline of RCI of more than 50% in any participant.
Conclusions: The combination of AGS-004 and VOR was safe and well tolerated. Few participants showed a decrease in rca-HIV RNA, but no substantial impact on the replication competent reservoir was measured. Surprisingly, the induction of HIV-specific immune responses by AGS-004 was marginal and inconsistent across all participants. These results differ from what has been reported for AGS-004 elsewhere. It seems likely that more efficacious antiviral immune interventions and perhaps more effective latency reversal agents must be developed to allow clearance of persistent HIV infection.