Defective HIV RNA may explain lingering viremia on ART

Clinical Takeaway: In patients with persistent low-level viremia on stable ART, consider that detectable HIV RNA may arise from defective, noninfectious proviruses—particularly 5′-leader defects—rather than treatment failure; unnecessary regimen escalation may often be avoided with appropriate evaluation.

Low-level detectable HIV RNA on otherwise effective ART can trigger anxiety, additional testing, or treatment changes. New data suggest most of these cases may not reflect active, transmissible infection.

A multicenter analysis of blood samples from 52 people living with HIV on long-term antiretroviral therapy (ART) found that most cases of non-suppressible viremia are driven by defective viral RNA rather than ongoing replication.

Across samples collected from 2021–2025, investigators showed that ~95% of detectable HIV-1 RNA sequences contained defects, most commonly in the 5′-leader region, a critical segment required for viral packaging and replication. Mutations or deletions in this region prevented the production of infectious virus despite measurable RNA in plasma.

Non-suppressible viremia is rare—occurring in <1% of treated individuals—but can persist for years or occur even in patients who never achieve fully undetectable viral loads. The data suggest these signals often arise from a small number of long-lived T-cell clones releasing defective viral particles, rather than from viral rebound or treatment failure.

“We know that these defective proviruses cannot infect new cells, but they are still clinically relevant,” said senior author Francesco R. Simonetti, MD, PhD, noting that such findings could help avoid “extra visits, extra drugs, extra costs and tests.”

The team also highlighted a novel assay (CLAWS) capable of identifying 5′-leader defects in plasma, offering a potentially scalable approach for distinguishing benign viremia from clinically significant replication.

Over time, intact replication-competent viruses appear to be “pruned away” on ART, while defective variants persist—raising new questions about immune recognition and HIV reservoir biology.

Source: Box JR, et al. (2026, June 8). Nat Commun. 5' leader defects drive persistent HIV-1 viremia on long-term ART