2025

What is the title of your project and what is it focused on?

The title of my project is "HIV-1 Capsid Hijacks CPSF6 to Subvert the Innate Immune Response." Our team is focused on using in silico structure-guided drug design to develop a first-in-class inhibitor of the CFIm complex. The CFIm complex is a post-transcriptional regulator of gene expression with roles in innate immunity, stress signaling, and cancer. One member of the CFIm complex, CPSF6, is hijacked by HIV during the early phase of the lifecycle. This drug will be a critical tool to help understand how and why the virus targets the CFIm complex. We hypothesize that the virus disrupts CFIm complex function to transcriptionally reprogram an infected cell and enhance its permissivity to infection.

How does your project align with the Center’s objectives?

These studies will leverage the historic strength of the HARC Center in structural analysis of protein-protein interactions to develop novel small molecule disrupters of the human CFIm complex. The HARC Center has long focused on viral regulatory and accessory proteins and their role in subverting host antiviral defenses. This work extends that focus but introduces a unique perspective with the potential involvement of the capsid protein in transcriptional reprogramming. We hypothesize that HIV capsid recruits a member of the CFIm complex, CPSF6, in part to disrupt CFIm function and dampen innate immune signaling. Gene editing of primary cells will be used as controls during inhibitor development in coordination with the Genetic score. The project aligns closely with ongoing efforts in Project 2 (Regulation of HIV Transcription and Latency) and Project 3 (Genetics and Evolution of HIV Restriction Factors). It will directly benefit and contribute to the resources of the Genetics Core to advance its objectives. Additionally, the PI’s specialized skills in high-throughput in silico drug design and discovery may provide synergistic opportunities for other HARC Center projects through collaboration with the Structural Biology Core.

What do you hope to accomplish with your award?

Ideally, this award will lead to the discovery of a first-in-class small molecule inhibitor of the CFIm complex to not only better understand the role of this complex during HIV infection, but for broad use as a new tool compound by the biomedical research community. Ultimately, we hope that next-generation compounds could be developed as targeted interventions.

What inspires you most about your project/research?

As a newcomer to the exciting field of HIV research, I bring fresh perspective and a strong collaborative foundation to this work. While I have not previously held an NIH award for HIV-related studies, I have spent the past two years working closely with Dr. Judd Hultquist (Northwestern University) to pioneer first-in-class inhibitors of two other host complexes known to be targeted by HIV: the Super Elongation Complex (Cisneros et al. PLoS Pathogens 2024) and the PAF1 Complex (Soliman et al. Science Advances 2023). Building on these successful campaigns, I now propose to apply our established design strategies to develop a novel inhibitor against the CPSF6-containing CFIm complex – an innovative approach that could open new therapeutic avenues in the treatment of HIV and other diseases. It excites me to be able to bridge discoveries in basic science with interventions that might someday impact patient care and better human health.

What are your thoughts on the importance of continuing to build our understanding of HIV-host protein complexes and expanding therapeutic targets and treatment modalities for HIV/AIDS?

Advancing our structural understanding of HIV-host protein complexes is essential for identifying novel therapeutic targets and developing next-generation treatments for HIV. By elucidating how HIV exploits host proteins—particularly in physiologically relevant systems like primary human immune cells—we can uncover new vulnerabilities in the viral life cycle. This knowledge enables the rational design of antiviral therapies that disrupt critical host-pathogen interactions, targeting both viral replication and immune evasion mechanisms. Ultimately, this research extends beyond the pursuit of a cure. It represents a transformative approach to HIV management—one that enhances prevention strategies, refines therapeutic interventions, and improves long-term clinical outcomes. Such advances will have far-reaching impacts, benefiting not only individuals living with HIV but also global public health efforts to control the epidemic.