The primary barrier to an HIV cure is the reservoir of latently infected cells, which are rare, persist for decades during antiretroviral therapy, and remain undetected by the host immune system. A potential method for eliminating these reservoirs cells is the “kick and kill” approach, in which a latency reversing agent (LRA) is administered to “kick” the virus out of latency, inducing HIV expression. Now awake, the infected cell can be killed via cytopathic effects or immune responses, while antiretroviral therapy limits HIV spread.

The Marsden lab uses in vitro and in vivo experimental models to study HIV infection, reservoir formation, treatment, and cure approaches. This includes cell line and primary cell models of latent infection and in vivo humanized mouse models of HIV infection. We are particularly focused on developing new approaches to eliminate the latent reservoirs of HIV that allow the virus to persist through years of drug treatment.

Ultimately, our lab seeks to develop safer and more effective novel latency reversing compounds that balance HIV latency reversal and nonspecific immune activation for improved cure approaches.

Current Projects

Kick Optimization: PKC Modulators as Latency Reversing Agents

PKC modulators have proven capable of efficiently reversing HIV from latency in several preclinical models of HIV persistence and are thus promising leads (Marsden et al., 2017, 2020; Kim et al., 2022; Gama et al., 2017). PKC modulators diffuse into cells and bind to soluble cytosolic PKC forming a complex that in turn translocates to intracellular membranes and activates downstream kinases, ultimately activating NFkB, an important transcription factor for HIV expression.

Though regarded as efficacious latency reversing agents, PKC modulators have been shown to induce non-specific immune activation and have not been optimized for in vivo tolerability, hampering their use. Currently, we are working to develop analogs and slow-release prodrugs of naturally occuring PKC modulators and other classes of latency reversing agents (e.g. histone deacetylase inhibitors, BET-bromodomain inhibitors) in cell lines, primary cells, and humanized mouse models to improve the latency reversal capacity of these compounds while addressing these issues.

Kill Augmentation: Rejuvenating Exhausted T Cells through Autophagy Induction

Autophagy is the process by which a cell can degrade and recycle dysfunctional cellular components to promote its longevity. Induction of autophagy has been shown to reduce proinflammatory cytokine production caused by potent experimental latency reversal agents (such as PKC modulators) and rejuvenate exhausted HIV-specific T cells bearing chimeric antigen receptors (CARs). Hence, we are exploring the use of autophagy inducing compounds to make latency reversal agents safer and more effective in vivo and simultaneously improve the depletion of cells expressing HIV by CAR T-Cells.