Combination CRISPR, Antiretroviral Therapies Could Eliminate 100% of HIV

Article

At least 58% of mice treated with combined CRISPR therapies showed signs of complete HIV-1 viral elimination.

Combining 2 clustered regularly interspaced short palindromic repeats (CRISPR) gene editing therapies with antiretroviral therapy (ART) effectively eliminated human immunodeficiency virus type 1 (HIV-1) in humanized and infected mice, according to the results of a study published in PNAS. The dual CRISPR technology has 2 targets: The HIV-1 virus’s C-C chemokine receptor type 5 (CCR5) coreceptor, which enables HIV-1 entry into the cell; and the HIV-1 long terminal repeat (LTR)-Gag region of infected cells, which contains dormant viral DNA.1

“The excision of HIV-1 DNA and the inactivation of CCR5 was brought together using gene-editing technologies built on observations from reported cures in human patients [with HIV],” said study author Kamel Khalili, PhD, Laura H. Carnell professor and chair of the Department of Microbiology, Immunology, and Inflammation and director at the Lewis Katz School of Medicine, in a press release. “In the few instances of HIV cures in humans, the patients underwent bone marrow transplantation for leukemia, and the donor cells that were used carried inactivating CCR5 mutations.”2

However, the study authors noted that treatment with 1 CRISPR therapy and ART was not completely effective; it needed to be the sequential treatment of 2 CRISPR technologies and ART.1 Current HIV-1 treatments include ART and broadly neutralizing antibodies to reduce infectious virus. Unfortunately, they only reduce the virus, not eliminate it.

Since ART is limited because infection can continue to spread, the investigators decided to study the efficacy of 2 CRISPR formulations designed to block infection spread.1

During the trial, the humanized and infected mice were either treated with a long-acting slow-effective release (LASAR) ART and CRISPR CCR5, LASAR ART and HIV-1LTR-Gag, ART monotherapy, or the dual CRISPR technologies with LASER ART.

Treatment with ART, ART and CRISPR CCR5, or ART and HIV-1LTR-Gag were not significantly different in HIV-1 viral elimination. Only 1 of 6 mice treated with ART and 1 CRISPR technology (CRISPR-CCR5) had no viral DNA, and 2 of 7 treated with ART and 1 CRSIPR technology (CRISPR HIV-1) had no HIV-1 DNA.1

Conversely, ART and dual CRISPR treatment significantly increased HIV-1 elimination compared to ART with single CRISPR treatment. Among 10 mice treated with LASER ART and dual CRISPR therapies, 6 had no viral DNA in the spleen, gut, bone marrow (BM), lung, liver, kidney, and brain. Overall, 58% of mice treated with combination CRISPR-mediated antiretroviral therapies and ART had no signs of HIV-1 DNA.1

The CRISPR technology must excise all infected cells that contain dormant HIV-1 to prevent rebound. Although 42% of mice experienced viral rebound, the dual therapy was largely effective at complete elimination or viral reduction.1

“We demonstrate that further improvements in LASER ART and CRISPR for combinatorial editing of viral and strategically important cellular genes such as CCR5 in hu(manized) mice may achieve and serve as a proof-of-principle for further investigation toward clinical trials,” wrote study authors in the article.1

References

  1. Dash P, Chen C, Kaminski R, et al. CRISPR editing of CCR5 and HIV-1 facilitates viral elimination in antiretroviral drug-suppressed virus-infected humanized mice. PNAS. May 1, 2023. doi.org/10.1073/pnas.2217887120
  2. Midwest Medical Edition. Chances Of Eliminating HIV Infection Increased By LASER ART And Novel Dual Gene-Editing. News Release. May 2, 2023. Accessed May 4, 2-23. https://www.midwestmedicaledition.com/articles/chances-of-eliminating-hiv-infection-increased-by-laser-art-and-novel-dual-gene-editing
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