HIV Rev-Rev Response Element Activity Variation in Transmission and Latency

Project Summary/Abstract Advances in antiretroviral therapy have made ending the HIV pandemic an increasingly plausible prospect. Unfortunately, more than a million new HIV infections occur annually and no safe and scalable cure for HIV exists. Underlying these public health and clinical problems are the viral mechanisms by which HIV

adapts to new hosts and establishes and maintains a latent state in infected cells. This project takes a novel approach to understanding these pathologic processes by addressing how an essential viral regulatory mechanism contributes to HIV transmission and latency. The HIV Rev-Rev Response Element (RRE) system is a viral regulatory axis that is essential for

replication. Differences in Rev-RRE activity level are observed among primary isolates and impact replication kinetics and the relative expression of viral proteins. Rev-RRE variations in HIV and other complex retroviruses can directly impact pathogenesis and provide a mechanism by which the virus adapts to differing fitness

landscapes. Despite this, little is known about how Rev-RRE variation affects transmission capacity or how this system contributes to latency. This project interrogates these issues in three aims. First, the role of Rev-RRE variation in navigating the sexual transmission bottleneck is defined. Second, the contribution of the Rev-RRE

axis to latency establishment, maintenance, and reversal is explored. Third, the project investigates how Rev- RRE activity contributes to the anatomic distribution of the latent reservoir. In each aim, single genome HIV sequences acquired in well-defined clinical scenarios are used to identify unique Rev-RRE pairs. Then, a novel high-throughput fluorescence based assay is used to determine

the Rev-RRE functional activity of hundreds of primary isolates. By comparing Rev-RRE activity in single hosts over time or in single hosts in different anatomic compartments, Rev-RRE functional variation and the role for this in HIV pathogenesis can be determined. This project will improve the current understanding of viral processes that contribute to transmission

and latency. While both of these mechanisms are well studied, existing models of transmission fitness and latency do not include a contribution of Rev-RRE activity variation. Successful completion of the project holds out the prospect of future improved interventions for infection prevention. Ultimately, it may also advance a

cure by pointing to new ways to improve latency reversal.