A new gene-editing strategy uses an extraordinary protective ability to eradicate HIV-1 infection

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Ironically, the genetic changes that lead to a rare fatal disorder known as MOGS-CDG protect cells from virus infection. Now, scientists at the Louis Katz School of Medicine at Temple University have used this extraordinary protective ability in a new gene-editing strategy aimed at eliminating HIV-1 infection without any negative effects on cell death.

The new approach, described online April 28 in the journal Nature Molecular therapy – nucleic acidsis based on a combination of two gene-modifying constructs, one targeting HIV-1 DNA and the other targeting a gene called Waves – Defects that cause MOGS-CDG. In cells taken from people infected with HIV-1, Temple researchers showed that disrupting the virus’s DNA while also deliberately changing Waves It inhibits the production of infectious HIV-1 particles. This discovery opens new avenues in developing a treatment for HIV/AIDS.

Salim Waves Function is necessary to bind to glycosylation, a process by which certain cellular proteins made in the body are modified to make them stable and functional. However, glycosylation is enhanced by certain types of infectious viruses. In particular, viruses such as HIV, influenza, SARS-CoV-2, and hepatitis C, which are enclosed in a viral envelope, depend on glycosylated proteins to enter host cells.

In the new study, the principal investigators introduce Kamel Khalili, PhD, Laura Carnell Professor and Chair of the Department of Microbiology, Immunology, and Inflammation, director of the Center for Neuroscience and Gene Editing, director of the Comprehensive NeuroAIDS Center at Louis Katz Medicine, and Rafal Kaminski, PhD, assistant professor in the Center for Neuroscience. and gene editing at the Louis Katz School of Medicine, designing a genetic approach to power CRISPR exclusively for ADHD Waves Gene expression through DNA editing within immune cells harboring HIV-1 replication efficiency. Their new approach is expected to avoid any impact on the health of uninfected cells that retain normal MOGS gene function. Stimulation of the system in HIV-1-infected cells disrupted the glycan structure of the HIV-1 envelope protein, culminating in the production of non-infectious virus particles.

d said Khalili, who is also the senior researcher on the new study: “This approach is conceptually interesting.” “By reducing the ability of the virus to enter cells, which requires glycosylation, Waves It may offer another target, in addition to integrated viral DNA, to develop the next generation of CRISPR gene-editing technology to eradicate HIV. “

Dr. Kaminsky, Dr. Khalili, and Tricia H. Purdue, Ph.D., professor and vice chair of the Department of Microbiology, Immunology, and Inflammation and the Center for Neuroscience and Gene Editing at Temple and an expert in the use of non-human primate models of HIV-1, are working together to further evaluate effectiveness and safety of the CRISPR-MOGS strategy in preclinical studies. In previous work, the team showed that CRISPR-based technology can successfully remove viral DNA from infected non-human primate cells.

Other contributing researchers include Hong Liu, Chen Chen, Shuren Liao, and Shohreh Amini, Department of Microbiology, Immunology, and Inflammation, Center for Neuroscience and Gene Editing, Louis Katz School of Medicine at Temple University. Daniel K. Sohai, Conrad RY Cruz, and Catherine M. Pollard, Center for Cancer Research and Immunology, Children’s National Health System, George Washington University; Thomas J Craddick and Jennifer Gordon, Excision Biotherapeutics, San Francisco, CA; Anand Mehta, Stephan Grauzam, and James Dressman, Department of Cellular 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 in part by grants from the National Institutes of Health and the WW Smith Charitable Trust.

source:

Journal reference:

Liu, H.; et al. (2023) Strategically self-limited production of infectious HIV particles by CRISPR in permissive cells. Molecular therapy – nucleic acids. doi.org/10.1016/j.omtn.2023.04.027.

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