HIV remains a global challenge, with latent reservoirs that current antiretroviral treatments cannot exclude. The "Kick-and-Kill" strategy in HIV cure employs Latency Reversing Agents (LRAs) to awaken dormant HIV-infected cells ("kick") and then harnesses the immune system to clear these reactivated cells ("kill"). While the standalone "Kick-and-Kill" strategy has not yet achieved significant reservoir reduction, it is highlighting the potential of integrating neutralizing antibody treatments to synergistically target latent HIV reservoirs. The Histone Deacetylase inhibitor (HDACi), one of the most extensively studied LRAs, in conjunction with Immunovaccine, did lead to a reduction in reservoir sizes in clinical trials. However, the effect was modest and transient, emphasizing the limitations of HDACi in this combinatorial approach.
Additionally, it has been observed that HDACi can adversely induce immune attenuation. Therefore, enhancing the latency reversal efficacy of HDACi is crucial, and subsequent immune stimulations are essential. This project aims to explore the potential of a novel triple combination of HDACi, Poly (ADP-ribose) polymerase inhibitor (PARPi), and Immune Checkpoint Inhibitor (ICI) to activate these latent HIV reservoirs and additionally enhance the host immune response to clear the infected cells. Drawing from their promising data acquired from HIV latently infected cell lines, J-Lat cells, and underpinned by robust rationale from cancer research, this study endeavors to transition the findings from cell line models to primary human cells. This transition is significant given that, unlike immortalized cell lines, primary human cells more closely mimic the physiological, genetic, and morphological characteristics of in-vivo conditions.
Dr. Izumi and his team have preliminarily confirmed the efficacy of their combination drug in reducing latent cell populations in human primary cell model. Statistically validating their findings with additional donors bolsters their confidence in the potential efficacy of their proposed therapy, paving the way for further ex-vivo and in-vivo studies crucial for advancing to clinical trials. In this study, they will assess the combined effects of these drugs on HIV latency reversal and immune cell activation in human PBMCs. Two specific aims are laid out:
- Specific Aim 1) Latency reversal efficacy, including Identification of responsible genes for latency reversal
- Specific Aim 2) Synergistic effect of immune activation, in primary human PBMC.
Using all FDA-approved drugs, positive results could accelerate their incorporation into HIV therapies. Validating preliminary findings in primary human cells is an essential step before advancing to ex-vivo and in-vivo experiments and eventually clinical trials.
Project Summary provided by investigator.