Defining the Landscape of Transcriptional Activity during HIV-1 Infection

DELTA-HIV (Defining the Landscape of Transcriptional Activity during HIV-1 Infection) addresses a central barrier to curing HIV: the persistence of transcriptionally silent but reactivatable proviruses in latently infected CD4⁺ T cells. Current cure strategies have limited efficacy, in part because transcriptional competence is poorly defined and standard assays rely on indirect, steady-state RNA measurements that miss early or abortive activity. This Fellowship will apply nascent transcriptomic approaches, specifically PRO-Seq, to resolve HIV-1 transcriptional dynamics at nucleotide resolution. Three interlinked work packages will: (1) map host and viral nascent transcription during infection and define how accessory proteins (Vpu/Vpr) rewire RNA polymerase II activity; (2) quantify Pol II dynamics at integrated proviruses in primary CD4⁺ latency models to identify predictive markers of reactivation; and (3) benchmark the rebound potential of latent reservoirs in people living with HIV (PLWH) using paired nascent and mRNA-Seq with integration-normalised analysis. DELTA-HIV directly addresses key knowledge gaps, seeking to refine biomarker discovery, inform therapeutic targeting, and advance global HIV cure strategies in line with Horizon Europe’s goals to reduce the burden of infectious disease.