Assessing the impact of AGS-004, a dendritic cell-based immunotherapy, and vorinostat on persistent HIV-1 Infection

Sci Rep. 2020 Mar 20;10(1):5134. doi: 10.1038/s41598-020-61878-3.

Abstract

Approaches to deplete persistent HIV infection are needed. We investigated the combined impact of the latency reversing agent vorinostat (VOR) and AGS-004, an autologous dendritic cell immunotherapeutic, on the HIV reservoir. HIV+, stably treated participants in whom resting CD4+ T cell-associated HIV RNA (rca-RNA) increased after VOR exposure ex vivo and in vivo received 4 doses of AGS-004 every 3 weeks, followed by VOR every 72 hours for 30 days, and then the cycle repeated. Change in VOR-responsive host gene expression, HIV-specific T cell responses, low-level HIV viremia, rca-RNA, and the frequency of resting CD4+ T-cell infection (RCI) was measured at baseline and after each cycle. No serious treatment-related adverse events were observed among five participants. As predicted, VOR-responsive host genes responded uniformly to VOR dosing. Following cycles of AGS-004 and VOR, rca-RNA decreased significantly in only two participants, with a significant decrease in SCA observed in one of these participants. However, unlike other cohorts dosed with AGS-004, no uniform increase in HIV-specific immune responses following vaccination was observed. Finally, no reproducible decline of RCI, defined as a decrease of >50%, was observed. AGS-004 and VOR were safe and well-tolerated, but no substantial impact on RCI was measured. In contrast to previous clinical data, AGS-004 did not induce HIV-specific immune responses greater than those measured at baseline. More efficacious antiviral immune interventions, perhaps paired with more effective latency reversal, must be developed to clear persistent HIV infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • CD4-Positive T-Lymphocytes / immunology
  • Dendritic Cells / transplantation*
  • HIV Infections / therapy*
  • HIV-1 / drug effects*
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Humans
  • Immunologic Memory / immunology
  • Immunotherapy, Adoptive / methods*
  • Male
  • Middle Aged
  • T-Lymphocytes, Cytotoxic / immunology
  • Translational Medical Research
  • Treatment Outcome
  • Vaccination
  • Vorinostat / therapeutic use*

Substances

  • Histone Deacetylase Inhibitors
  • Vorinostat