A multipronged, mRNA gene therapy approach to HIV cure

CHALLENGE: Pathogen persistence within a host results in lifelong infection and causes significant morbidity and mortality. Viruses that endure, like HIV-1, evade clearance by establishing latent infection and escaping immune responses. Latency is a reversible form of nonproductive infection in which virus transcription is suppressed. As such, latent viruses fly under the radar of the host immune surveillance. Previously tested latency reversal strategies have failed due to inadequate potency and off-target toxicity. Further, HIV-1 evades host immune responses through its extreme genetic diversity and direct immune dysregulation. While passive antibody and cellular immunotherapy have shown promise in clearing virus, efficient, cost-effective delivery of these interventions has hampered their use. “Kick and kill” cure strategies, which have not been effective to date, seek to combine latency reactivation (“kick”) with interventions that clear reactivated virus (“kill”). APPROACH: mRNA gene therapy has revolutionized vaccine development and is poised to address shortcomings described above. As opposed to other technologies, mRNA does not come with risk of insertional mutagenesis or require serologic prescreening. Importantly, its production uses cell-free procedures, remains inexpensive at scale, and is both flexible and rapid. mRNAs encoding any gene of interest are delivered in lipid nanoparticles (LNPs) that can be engineered to target specific cell types for timed, transient protein expression. To address shortcomings in existing HIV Cure strategies, I have recently developed three novel mRNA-based approaches: CD4-targeted delivery of the viral protein Tat, which drives HIV-1 transcription; hepatic delivery of mRNA encoding monoclonal antibodies that are secreted into circulation; and chemokine-targeted mRNA delivery to effector immune subsets. Here, I propose to develop these approaches as novel platforms that can be combined into the first mRNA-only kick and kill cure strategy. INNOVATION: In this application, I outline an interdisciplinary research program in which I design, study, and apply cutting edge mRNA gene therapy to tackle previously insurmountable obstacles to an HIV cure. Using all aspects of my clinical and scientific training, I have designed interventions grounded in an understanding of both HIV-1 and human biology and tailored my delivery vehicle to suit this application. But, these approaches will find application elsewhere; as they are developed, I envision applying these tools to disrupt viral transcriptional programs, deliver pathogen-specific antibodies, and modify host effector cells as interventions against other diseases. These novel mRNA-based approaches have the chance to translate the success of the mRNA-LNP platform from vaccines to HIV eradication with the potential for worldwide use. Project Number: 1DP2AI184637-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Edward Kreider | Institution: UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, PA | Award Amount: $486,057 | Activity Code: DP2 | Study Section: Special Emphasis Panel[ZAI1 VSR-D (M1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1DP2AI18463701