Molecular therapy. Nucleic acidsSep 11, 2026

Editing brain viral reservoirs in treated SIV-infected rhesus macaques

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 12, 2026

Abstract

SIV genomes were detected in multiple brain regions of rhesus macaques, confirming the CNS as a persistent reservoir during ART.

Latent HIV-1 reservoirs in the central nervous system may contribute to HIV-associated neurocognitive disorders despite antiviral treatment.
CRISPR technology delivered via AAV9 has shown the ability to edit proviral DNA in peripheral tissues with acceptable safety.
Infected macaques treated with AAV9-CRISPR demonstrated measurable proviral editing across different regions of the brain.
Analysis of the SIV genomes indicated compartmentalized persistence in the central nervous system.
These results highlight the potential for genome editing as a strategy to target CNS reservoirs in HIV infection.

Simplified

Latent human immunodeficiency virus type 1 (HIV-1) reservoirs in the central nervous system (CNS) may sustain viral persistence and neuroinflammation contributing to HIV-associated neurocognitive disorders (HAND) despite suppressive ART. AAV9-delivered CRISPR has successfully edited SIV proviral DNA in peripheral tissues with acceptable safety profiles, but the extent of in vivo genome editing in the brain remains unclear. Using SIV-infected rhesus macaques, we mapped intact proviral DNA across CNS regions and tested systemic AAV9-CRISPR-Cas9 targeting conserved sites within Ψ packaging signal and Gag region. Ten adult rhesus macaques were infected with genetically barcoded SIVmac239, suppressed with ART, then randomized to receive intravenous AAV9-SaCas9 with dual gRNAs (Ψ + Gag) or a Cas9-only control. At necropsy after viral rebound, SIV genomes were detected in multiple brain regions as well as lymphoid tissues, confirming the CNS as a persistent reservoir during ART. Barcode analysis revealed region-specific patterns consistent with compartmentalized CNS persistence. In CRISPR-treated animals, proviral editing was measurable across anatomically distinct CNS sites. These findings demonstrate that intact and potentially replication-competent virus persists in the primate brain under ART and that systemic AAV9-CRISPR can reach and edit proviral DNA in this sanctuary, supporting genome editing as a strategy toward durable remission of CNS reservoirs.

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Editing brain viral reservoirs in treated SIV-infected rhesus macaques

Abstract

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