HIV Targets R-Loops To Integrate Into Host DNA, Study Finds

A new study by researchers at the German Center for Infection Research (DZIF) and Heidelberg University Hospital has identified RNA:DNA hybrids, known as R-loops, as structural features that guide the integration of HIV-1 into the human genome. The work reveals a previously unrecognized mechanism in the viral life cycle and highlights a potential vulnerability that could be exploited to limit or redirect viral integration.

The findings were published in Nature Microbiology.

Antiretroviral therapies (ARTs) have significantly improved outcomes for people living with HIV. However, these treatments must be taken continuously, and interruptions—whether due to access, supply issues or adherence—can result in rapid viral rebound and drug resistance. One of the main reasons for this persistence is the formation of latent viral reservoirs, which are created when HIV integrates its genome into that of host immune cells.

The integration process is carried out by the HIV-1 integrase enzyme, but the factors that guide where in the genome the virus inserts itself have not been fully understood. The latest research uncovers how HIV-1 is directed toward specific non-coding regions of actively transcribed genes through interactions with R-loops.

R-loops identified as genomic signposts

The study shows that HIV-1 does not integrate randomly into the host genome. Instead, the virus preferentially targets R-loops, which are RNA:DNA hybrid structures that arise during gene transcription. These structures were mapped in immune cells, and integration events were found to coincide with their locations.

The researchers identified that the cellular enzyme Aquarius plays a crucial role in this targeting process. Aquarius, a helicase involved in RNA splicing, binds to HIV-1 integrase and facilitates access to the R-loops by unwinding them. When Aquarius expression was reduced, HIV-1 integration rates dropped significantly and were redirected away from R-loop-rich regions. This suggests a functional role for the enzyme in HIV-1 genome integration.

A pathway to future treatments

By establishing the molecular details of HIV-1’s integration preferences, the study provides new targets for therapeutic intervention. While ART can suppress viral replication, it does not eliminate cells containing integrated virus. Strategies that interfere with the R-loop targeting mechanism could, in future, contribute to reducing the establishment or stability of viral reservoirs.

Collaborative research effort

The research was led by DZIF investigator Dr. Marina Lusic at the Center for Integrative Infectious Disease Research (CIID), part of Heidelberg University Hospital. It involved contributions from scientists specializing in bioinformatics, structural biology and retrovirology, based at institutions in Zagreb, Padua, London and Bordeaux. The study was supported by DZIF and the German Research Foundation (DFG) through the Special Collaborative Programme SFB 1129.

Reference: Penzo C, Özel I, Martinovic M, et al. Aquarius helicase facilitates HIV-1 integration into R-loop enriched genomic regions. Nat Microbiol. 2025. doi:10.1038/s41564-025-02089-2

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