Comparison of latent activation between subtypes B and C of HIV

The National Institute of Allergy and Infectious Diseases awarded the University of Louisville $109,361 on November 29, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to compare latent viral activation between HIV subtypes B and C.

The research investigates whether latent HIV reservoir composition and proviral inducibility differ between HIV-1B, the most-studied subtype, and HIV-1C, the most prevalent globally. The work examines differential responsiveness to NF-kB-targeting latency reversal agents used in "kick-and-kill" cure strategies, hypothesizing that subtype-specific variation in transcription factor binding sites within integrated viral sequences may enable subtype-specific precision therapeutic approaches. This research directly addresses a documented surge of non-B HIV in Kentucky and Ohio, a threat to the Department of Health and Human Services "End the HIV Epidemic" 2030 agenda.

Performance occurs in Louisville, Kentucky with an ultimate completion date of June 30, 2030. The award is classified as a Project Grant. The University of Louisville's Office of Research & Innovation administers the funding.

Abstract

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS) and is a key source of global morbidity and mortality. HIV subtype B (HIV-1B) is the most studied HIV subtype and is thought to be the most common in the western world despite only representing ~10% of global infection. Assumptions of parity between HIV-1B and other subtypes have often failed to incorporate known differences in pathogenesis, antiretroviral therapy efficacy, and cell tropisms of non-B subtypes, widening disparities in the study of non-B HIV infection. Domestically, intravenous drug use-associated HIV transmission is a key driver of new infections and is highly associated with viral recombination. Recent data documented a surge of non-B HIV in kentucky and ohio - a potentially fatal, unaccounted-for threat to the department of health and human services "end the HIV epidemic" 2030 agenda. In all subtypes, current treatments slow progression but do not cure the infection because of the persistence of a latent viral "reservoir" (LVR) that RE-seeds infection upon therapy interruption. Given that viral transcription is initiated by CO-opting of host transcription factors, subtype-specific differences in NF-ΚB transcription factor binding sites in the long terminal repeats (LTRS) of integrated viral sequences may be differentially inducible in ways that can be targeted for precision cure. IT remains unknown if LVR composition (e.g. integration sites and proviral integrity) differ between the most-studied HIV-1B and the most prevalent HIV subtype C (HIV-1C). Likewise, differential responsiveness to NF-ΚB targeting latency reversal agents (LRAS) - used in "kick-and-kill" cure strategies - has not been examined across subtypes. Taken together, this proposal hypothesizes that HIV-1B and HIV-1C LVR variation drives differential proviral inducibility by NF-ΚB-targeting LRAS and may inform subtype-specific cure potential. This hypothesis will be addressed through two aims: 1) defining variation between HIV-1B and HIV-1C LVR composition, and 2) characterizing subtype-specific LRA reactivation potentials. This project will expand our understanding of HIV subtype-specific biology and address knowledge gaps that could inform HIV cure research. Confirmation of HIV-1C deviation from HIV-1B in either aim represents avenues for novel treatment paradigms, and confirmation of this deviation in both aims suggests that HIV-1C has a smaller and more reactive LVR that would encourage its prioritization for targeted cure efforts. The applicant, MR. Steven nadakal, is an MD-PHD student training with the primary sponsor, DR. Melissa smith, an associate professor in the department of biochemistry and molecular genetics (BMG) at the university of louisville school of medicine (ULSOM). He is CO-sponsored by DR. Eric rouchka, a pioneering bioinformatician and professor in BMG. This work will advance MR. Nadakal's conceptual and technical expertise in virology, immunology, bioinformatics, and genomics for use as an infectious disease physician-scientist.