Genetic alterations that give rise to a rare, fatal disorder often known as MOGS-CDG paradoxically also protect cells against infection by viruses. Now, scientists on the Lewis Katz School of Medicine at Temple University have harnessed this unusual protective ability in a novel gene-editing strategy geared toward eliminating HIV-1 infection with no hostile effects on cell mortality.

The brand new approach, described online April 28 within the journal Molecular Therapy – Nucleic Acids, is predicated on a mix of two gene-editing constructs, one which targets HIV-1 DNA and one which targets a gene called MOGS – defects wherein cause MOGS-CDG. In cells from individuals infected with HIV-1, the Temple researchers show that disrupting the virus’s DNA while also deliberately altering MOGS blocks the production of infectious HIV-1 particles. The invention opens up recent avenues in the event of a cure for HIV/AIDS.

Proper MOGS function is crucial for glycosylation, a process by which some cellular proteins synthesized within the body are modified to make them stable and functional. Glycosylation, nonetheless, is leveraged by certain sorts of infectious viruses. Specifically, viruses like HIV, influenza, SARS-CoV-2, and hepatitis C, that are surrounded by a viral envelope, depend on glycosylated proteins to enter host cells.

In the brand new study, lead investigators Kamel Khalili, PhD, Laura H. Carnell Professor and Chair of the Department of Microbiology, Immunology, and Inflammation, Director of the Center for Neurovirology and Gene Editing, and Director of the Comprehensive NeuroAIDS Center on the Lewis Katz School of Medicine, and Rafal Kaminski, PhD, Assistant Professor on the Center for Neurovirology and Gene Editing on the Lewis Katz School of Medicine designed a genetic approach to exclusively activate CRISPR to impede MOGS gene expression through DNA editing inside immune cells that harbor replication competent, HIV-1. Their novel approach is anticipated to avoid any impact on the health of uninfected cells that retain normal MOGS gene function. Stimulation of the apparatus in HIV-1 infected cells disrupted the glycan structure of the HIV-1 envelope protein, culminating within the production of non-infectious virus particles.

“This approach is conceptually very interesting,” said Dr. Khalili, who can also be senior investigator on the brand new study. “By mitigating the power of the virus to enter cells, which requires glycosylation, MOGS may offer one other goal, along with the integrated viral DNA for developing the subsequent generation of CRISPR gene-editing technology for HIV elimination.”

Dr. Kaminski, Dr. Khalili, and Tricia H. Burdo, PhD, Professor and Vice Chair within the Department of Microbiology, Immunology, and Inflammation and the Center for Neurovirology and Gene Editing at Temple and an authority in using non-human primate models for HIV-1, have been working together to further assess the efficacy and safety of CRISPR-MOGS strategy in preclinical studies. In previous work, the team demonstrated that CRISPR-based technology can successfully remove viral DNA from the cells of infected non-human primates.

Other researchers who contributed to the study include Hong Liu, Chen Chen, Shuren Liao, and Shohreh Amini, Department of Microbiology, Immunology, and Inflammation, Center for Neurovirology and Gene Editing, Lewis Katz School of Medicine at Temple University; Danielle K. Sohaii, Conrad R.Y. Cruz, and Catherine M. Bollard, Center for Cancer and Immunology Research, Kid’s National Health System, The George Washington University; Thomas J. Cradick and Jennifer Gordon, Excision Biotherapeutics, San Francisco, CA; Anand Mehta, Stephane Grauzam, and James Dressman, Department of Cell and Molecular Pharmacology, Medical University of South Carolina; and Carlos Barrero and Magda Florez, Department of Pharmaceutical Sciences, School of Pharmacy, Temple University.

The research was supported partially by grants from the National Institutes of Health and the W.W. Smith Charitable Trust.

Source:

Temple University Health System

Journal reference:

Liu, H., et al. (2023) Strategic Self-Limiting Production of Infectious HIV Particles by CRISPR in Permissive Cells. Molecular Therapy — Nucleic Acids. doi.org/10.1016/j.omtn.2023.04.027.