Intact HIV Proviruses Persist in the Brain Despite Viral Suppression with ART

While antiretroviral therapy (ART) effectively suppresses HIV in the blood, the central nervous system (CNS) is a distinct anatomical compartment that is difficult to treat. Researchers sought to determine whether the brain acts as a stable, long-term reservoir for HIV and whether this reservoir contains intact, potentially replication-competent viral genomes in individuals who have achieved long-term viral suppression.

The researchers analyzed autopsy frontal lobe tissue from 18 viremic and 12 virologically suppressed individuals with HIV, alongside 6 HIV-seronegative controls. They utilized the Intact Proviral DNA Assay (IPDA), a sophisticated droplet digital PCR (ddPCR) method, to distinguish between intact HIV proviruses and those with fatal defects. To confirm the cellular source of the virus, they used in situ hybridization (DNAscope) and laser capture microdissection to isolate and sequence HIV DNA from CD68+ myeloid cells (microglia and macrophages) within the brain parenchyma.

The study found that total HIV DNA levels in the brain were similar between viremic and ART-suppressed individuals, indicating that the CNS reservoir is stable and largely unaffected by systemic ART. Crucially, the researchers detected intact HIV proviruses in the majority of both viremic and virally suppressed participants. These intact genomes were found in the brain parenchyma, specifically within resident CD68+ myeloid cells, confirming that the brain is a true resident reservoir. The composition of these proviruses—the ratio of intact to defective genomes—was found to be similar to that observed in peripheral lymphoid tissues.

These findings demonstrate that the CNS is a persistent, independent reservoir of HIV that survives despite long-term ART. The presence of intact proviruses suggests that the brain could be a source of viral rebound if therapy is interrupted. Furthermore, the persistence of defective proviruses, which can still express neurotoxic proteins like Tat and Nef, may contribute to the chronic inflammation and neurocognitive disorders frequently observed in people with HIV, even when systemic viral loads are undetectable.