Chances of eliminating HIV infection increased with new double gene-editing approach – ScienceDaily

“The idea of ​​using gene-editing techniques to combine HIV-1 DNA excision with CCR5 inactivation is based on observations from reported cures in human HIV patients,” says Laura H. Carnell. Dr. Kamel Khalili, Professor and Chair of the Department, said. PhD in Microbiology, Immunology, and Inflammation, Lewis Katz School of Medicine, Director of the Center for Neurovirology and Gene Editing, and Director of the Comprehensive NeuroAIDS Center. “In one of the few examples of human HIV cure, a patient underwent a leukemia bone marrow transplant and the donor cells used had an inactivating CCR5 mutation.”

Dr. Khalili and Howard E. Gendelman, MD, professor in the Department of Pharmacology and Empirical Neuroscience at UNMC, were senior investigators in this new study. The two researchers have been longtime collaborators and have strategically combined their research strengths to find a cure for HIV.

“We are true partners and what we have achieved here is truly amazing,” said Dr. Gendelman. “Dr. Kalili’s team generated the requisite gene-editing constructs, applied them to a laser-art mouse model in Nebraska, determined when to administer gene-editing therapy, and performed HIV-1 ablation, CCR5. We performed analyzes to maximize inactivation, and suppression of viral multiplication.”

In the previous work, Dr. Khalili and Gendelman and their respective teams have shown that HIV is edited out of the genome of live humanized HIV-infected mice, leading to cures in some animals. For that study, Dr. Khalili and collaborator Dr. Rafal Kaminski, an assistant professor in the Center for Neurovirology and Gene Editing at Katz Medical School, brought their expertise in CRISPR gene-editing technology to target HIV-1. A therapeutic strategy known as long-acting extended-release (LASER) antiretroviral therapy (ART), co-developed by Dr. Gendelman and Dr. Benson Edagwa, Assistant Professor of Pharmacology at UNMC. LASER ART keeps HIV replication at low levels for a long time and reduces the frequency of ART administration.

Despite being able to eliminate HIV in LASER-ART mice, researchers found that HIV could eventually re-emerge from tissue reservoirs and cause rebound infection. This effect mimics rebound infection in human patients who have been on ART but who abruptly stop or discontinue treatment. HIV integrates its DNA into the host cell genome and can remain dormant for long periods in tissue reservoirs out of reach of antiretroviral drugs. As a result, when ART is stopped, HIV replication is renewed and AIDS occurs.

To prevent rebound infection, Dr. Kalili and colleagues begin research into next-generation CRISPR technology for HIV ablation, developing a novel dual system aimed at permanently eliminating HIV from animal models. Did. “The success story of a human HIV patient who underwent a bone marrow transplant for leukemia and was cured of HIV led us to hypothesize that loss of his CCR5, the receptor for the virus, was critical to permanently eliminate HIV infection. he explained. They developed a simpler and more practical procedure for inactivating CCR5, including his IV inoculation of CRISPR gene-editing molecules.

Experiments in humanized LASER-ART mice conducted by Dr. Gendelman’s team showed that co-administration of the Temple-developed constructs resulted in viral suppression, restoration of human T cells, and replication of HIV-1 in 58% of infected individuals. was shown to result in the removal of animal. This finding supports the idea that CCR5 plays an important role in facilitating HIV infection.

Temple’s team also plans to test the dual gene-editing strategy in non-human primates soon. To that end, Dr. Kaliri has her Tricia H. Burdo, Ph.D., professor and vice chair of the Department of Microbiology, Immunology, and Inflammation at Katz College of Medicine, an expert known for the use of non-human primate models. cooperate with For her work on HIV-1, who was also a co-author of the new study. Dr. Burdo and her team are interested in understanding her CCR5 involvement in SIV-infected primates. Her lab has previously played a key role in studies demonstrating the efficacy and safety of her CRISPR-based technology in removing her HIV DNA from primate cells.

A novel dual CRISPR gene-editing strategy holds great promise for human HIV therapy. “It’s a simple and relatively inexpensive approach,” said Dr. Kariri. “The type of bone marrow transplantation that has resulted in a cure in humans is reserved for leukemia patients. not applicable.”

“Curing HIV is the big picture,” Dr. Gendelman added. “Through our ongoing collaboration, Temple and his UNMC have been able to conduct meaningful research and ultimately impact the lives of many.”

In addition to Rafal Kaminski, researchers such as Prasanta K. Dash, Hang Su, Brady Sillman, Chen Zhang, Sruthi Sravanam, Emiko Waight, Lili Guo, Saumi Mathews, R. Lee Mosley, Larisa Y. Poluektova, and Santhi contributed to this work. contributes to Department of Pharmacology and Experimental Neuroscience, UNMC. Cheng Cheng, Pietro Mancuso, Shuren Liao, Hong Liu, Larsan Sarya, Maurizio Caocci, Chohré Amini, Neurovirology and Gene Editing Center, Microbiology, Immunology, Inflammation, Temple University Louis Katz medical college.

This work was supported by the National Institutes of Health including grants T32NS105594, 5R01MH121402, 1R01Al158160, R01DA054535, 1041 R01NS126089, R01 AI145542, R01NS36126, R01MH115860, 1R33DA04101. 8, 1042, and 2R01NS034239 (UNMC), and T32MH079785, P30MH092177, and UM1AI164568 (Lewis Katz School of Medicine).