Hypermutated HIV Proviruses Persist in All People Living with HIV on Antiretroviral Therapy

Recent research from Simon Fraser University has shed new light on the persistence of hypermutated proviruses in people living with HIV, despite antiretroviral therapy (ART). The study, published in the journal Virus Evolution, found that hypermutated proviruses, which arise from the action of host antiviral APOBEC3 proteins, are present in all individuals receiving ART. These hypermutated sequences have been routinely excluded from phylogenetic analysis due to their extensive mutations, but researchers have developed a simple phylogenetic approach to analyze them. The study revealed that hypermutated proviruses can persist for decades, and their age distributions suggest that different provirus types decay at heterogeneous rates in some hosts.

Key Takeaways:

• Hypermutated proviruses, which arise from the action of host antiviral APOBEC3 proteins, persist in all people living with HIV on antiretroviral therapy (ART).
• Researchers have developed a simple phylogenetic approach to analyze hypermutated proviruses, which enables the reconstruction of phylogenies and inference of their within-host evolutionary origins and dynamics.
• The approaches used normalized tree topologies, eliminated erroneous clustering of hypermutated proviruses, and brought env-intact and hypermutated proviruses into comparable ranges with respect to multiple tree-based metrics.
• Subsequent molecular dating of hypermutated proviruses revealed that they span a wide within-host age range, with the oldest ones dating to shortly after infection.
• The study suggests that hypermutated proviruses, like other provirus types, begin to be seeded into the proviral pool immediately following infection and can persist for decades.
• The research has implications for understanding HIV persistence during ART and the development of new therapies.

Statistics:

• 1400 longitudinal single-genome-amplified HIV env-gp120 sequences were isolated from six women over a median of 18 years of follow-up.
• 500 proviruses were isolated over a median of 9 years on ART.
• The median duration of follow-up between seroconversion and ART initiation was 9 years.
• The median age of the oldest hypermutated proviruses was shortly after infection.
• The study included six participants with hypermutated proviruses that differed in their age distributions.

Sources:

• A simple phylogenetic approach to analyze hypermutated HIV proviruses reveals insights into their dynamics and persistence during antiretroviral therapy. Virus Evolution, 2024,11(1).
• NewsRx. Research Reports on HIV/AIDS from Simon Fraser University Provide New Insights (A simple phylogenetic approach to analyze hypermutated HIV proviruses reveals insights into their dynamics and persistence during antiretroviral therapy). AIDS Weekly. October 20, 2025; p 170.