Strategic self-limiting production of infectious HIV particles by CRISPR in permissive cells
Molecular therapy. Nucleic acids
CRISPR gene editing; CRISPR prevention of viral entry; HIV infection; MT: RNA/DNA Editing; combined gene editing for HIV cure; glycosylation; mannosyl oligosaccharide glucosidase (MOGS); non-infectious virus production
Post-translational glycosylation of the HIV-1 envelope protein involving precursor glycan trimming by mannosyl oligosaccharide glucosidase (MOGS) is critically important for morphogenesis of virions and viral entry. Strategic editing of the MOGS gene in T lymphocytes and myeloid origin cells harboring latent proviral DNA results in the production of non-infectious particles upon treatment of cells with latency reversal agents. Controlled activation of CRISPR-MOGS by rebound HIV-1 mitigates production of infectious particles that exhibit poor ability of the virus to penetrate uninfected cells. Moreover, exclusive activation of CRISPR in cells infected with HIV-1 alleviates concern for broad off-target impact of MOGS gene ablation in uninfected cells. Combination CRISPR treatment of peripheral blood lymphocytes prepared from blood of people with HIV-1 (PWH) tailored for editing the MOGS gene (CRISPR-MOGS) and proviral HIV-1 DNA (CRISPR-HIV) revealed a cooperative impact of CRISPR treatment in inhibiting the production of infectious HIV-1 particles. Our design for genetic inactivation of MOGS by CRISPR exhibits no detectable off-target effects on host cells or any deleterious impact on cell survival and proliferation. Our findings offer the development of a new combined gene editing-based cure strategy for the diminution of HIV-1 spread after cessation of antiretroviral therapy (ART) and its elimination.
Liu, Hong; Chen, Chen; Liao, Shuren; Sohaii, Danielle K.; Cruz, Conrad R.; Burdo, Tricia H.; Cradick, Thomas J.; Mehta, Anand; Barrero, Carlos; Florez, Magda; Gordon, Jennifer; Grauzam, Stephane; Dressman, James; Amini, Shohreh; Bollard, Catherine M.; Kaminski, Rafal; and Khalili, Kamel, "Strategic self-limiting production of infectious HIV particles by CRISPR in permissive cells" (2023). GW Authored Works. Paper 2724.