Role of the REV-REV response element regulatory axis in HIV transmission - research summary

The National Institute of Allergy and Infectious Diseases awarded the University of Virginia $282,625 on June 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the role of the Rev-Rev response element regulatory axis in HIV transmission.

The research explores how variation in Rev-Rev response element (RRE) activity contributes to HIV sexual transmission and the underlying molecular mechanisms of RRE function in primary isolates. The Rev-RRE regulatory axis plays a crucial role in HIV replication and the export of intron-retaining viral messenger RNAs from the nucleus. Prior data from female-to-male transmission dyads indicated that subtype C transmitted-founder variants display lower RRE activity compared to donor quasispecies, suggesting selection bias on the basis of RRE function at the transmission bottleneck. This award funds evaluation of the generalizability of that finding to other transmission contexts and HIV subtypes. Research will assess changes in RRE activity across acute through chronic infection quasispecies using longitudinal samples obtained from individuals who acquired HIV via different transmission routes.

The award period runs from June 1, 2026, through May 31, 2028, with work performed in Charlottesville, Virginia. This is a Project Grant under the Allergy and Infectious Diseases Research program, which supports biomedical research and research training in infectious diseases and related areas at public and private nonprofit institutions.

HIV continues to pose a significant global health threat, despite the effectiveness of treatment. A deeper understanding of HIV transmission mechanisms could lead to novel interventions that reduce new infections. Sexual transmission of HIV is a complex process that involves overcoming host tissue barriers and immune responses, with the vast majority of new infections being caused by a single viral variant. Certain viral characteristics improve fitness at the transmission bottleneck, but the selected phenotype of the transmitted/founder variant is incompletely described. The REV-REV response element (RRE) regulatory axis plays a crucial role in HIV replication and is required for the export of intron-retaining viral mrnas from the nucleus. Variations in this system may allow viral variants to adapt to different fitness landscapes. HIV isolates exhibit functional differences in the REV-RRE system that impact replication kinetics and viral protein production. These variations in REV-RRE activity may contribute to the success of specific viral variants during transmission. Data from female-to-male transmission dyads indicates that subtype c transmitted-founder variants display lower REV-RRE activity compared to the donor quasispecies. This observation suggests a selection bias on the basis of REV-RRE function in the transmission bottleneck in this specific context. This proposal explores the generalizability of this finding to other transmission contexts and HIV subtypes as well as the underlying molecular mechanisms of REV-RRE activity variation in primary isolates. Aim 1: evaluate how variation in REV-RRE activity contributes to HIV sexual transmission. Using longitudinal samples obtained from individuals who acquired HIV via different transmission routes, changes in REV-RRE activity acute through chronic infection quasispecies will be assessed. This will enable identification of selection on REV-RRE activity during sexual transmission across a robust data set. Aim 2: investigate the molecular mechanisms behind variation in REV-RRE activity. Using primary isolates, the contributions of ENV activity, nuclear export of unspliced viral RNA, and REV protein kinetics to REV-RRE activity variation will be assessed. These aims will provide important information on the role of the REV-RRE axis in HIV transmission, which could inform new therapeutic or prophylactic strategies targeting this system. Understanding the molecular basis of REV-RRE activity variation will also shed light on other HIV processes that may be impacted by this regulatory axis, such as viral persistence and reactivation.