HIV-1 mRNA Knockdown with CRISPR/Cas9 Enhances Neurocognitive Function

Area of Science:

• Neuroscience
• Gene Therapy
• Virology

Background:

• HIV-1 establishes persistent reservoirs in the central nervous system (CNS) within mixed glia.
• HIV-1 infection in the CNS can lead to HIV-associated neurocognitive disorders (HAND).
• CRISPR/Cas9 gene editing offers a potential strategy for targeting viral reservoirs.

Approach:

• Adeno-associated virus 9 (AAV9)-CRISPR/Cas9 was used to target HIV-1 mRNA in cortical mixed glia.
• Experiments were conducted both in vitro using neonatal HIV-1 transgenic rat glia and in vivo in HIV-1 transgenic rats.
• HIV-1 mRNA levels were quantified using in situ hybridization, and neurocognitive effects were assessed via temporal processing tests.

Key Points:

• In vitro studies showed dose-dependent decreases in HIV-1 mRNA in a subset of treated glia.
• In vivo treatment resulted in significant excision (approx. 53.2%) of HIV-1 mRNA in the medial prefrontal cortex (mPFC).
• CRISPR/Cas9 treatment partially restored the temporal processing abilities in HIV-1 transgenic rats.

Conclusions:

• Mixed glia are susceptible to AAV9-CRISPR/Cas9 gene editing for reducing HIV-1 mRNA.
• CRISPR/Cas9 demonstrates potential as a therapeutic strategy for HAND, even without complete viral eradication.
• Further research is warranted to explore the full therapeutic potential of gene editing for neurological complications of HIV-1 infection.