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

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.

Self-amplifying RNA vaccines for infectious diseases

“…An RNA (AGS-004) encoding multiple HIV-1 proteins and the CD40 ligand (CD40L) was tested in phase I and IIB clinical trials [113][114][115], but the vaccine did not reduce viral load or prevent viral rebound. When combined with the latency-reversing agent vorinostat, no substantial impact on the frequency of resting T-cell infection was observed [117]. A naked mRNA (iHIVRNA) encoding HIV-1 immunogens and the dendritic cell activator TriMix (CD40L, CD70, and caTLR4) was safe in a phase I trial, but did not show sufficient immunogenicity in a phase II trial which was recently terminated (NCT02888756) [118,119].…”

Curing HIV: Seeking to Target and Clear Persistent Infection

“…In this population, treated for a relatively short period of time after initial infection, the natural decay of persistent HIV DNA seen in early ART may have obscured a weak effect of the interventions. Initial reports of pilot studies employing similar approaches have also failed to achieve a measurable depletion of latent, persistent infection (Gay et al, 2020;B. Mothe et al, 2017, Conference on Retroviruses and Opportunistic Infections, abstract).…”

“…Emblematic of the early state of the field, few studies have paired LRAs with a viral clearance strategy (Table 1). In one pilot study (Fidler et al, 2020) and reports of two others employing broadly similar approaches (B. Mothe et al, 2017, Conference on Retroviruses and Opportunistic Infections, abstract;Gay et al, 2020), depletion of latent, persistent infection was not seen. Although latency reversal activity appears to be measurable as an increase in HIV RNA expression within circulating lymphocytes, it is unclear whether this response will translate to sufficiently robust and durable HIV-1 protein expression to enable immune clearance of infected cells.…”

In the Era of mRNA Vaccines, Is There Any Hope for HIV Functional Cure?

“…New approaches based on more innovative immunogens have been proposed, such as mRNA vaccines. To date, only a few HIV mRNA vaccines clinical trials have been conducted ( Table 2 ), most of them using transfected DCs [ 14 , 18 , 76 , 77 , 78 , 79 ] and another couple evaluating naked mRNA [ 80 , 81 ].…”