Scientists at the Lewis Katz School of Medicine at Temple University have taken a major step forward in HIV research as they have successfully edited SIV DNA from the genomes of non-human primates.
Advances in antiretroviral therapy (ART) have greatly limited replication of resident HIV-1. It has also reduced plasma viral load and improved immune system function in HIV positive patients. Nonetheless, ART cannot permanently eliminate the virus and cure the illness. People with HIV often experience viral load rebound within weeks of ART interruption. These individuals are also vulnerable to a broad range of comorbidities.
To compromise the integrity of the proviral DNA and as a result inactivate its expression, researchers at Temple University have spent the past five years adapting CRISPR methods for targeting and editing various regions within the HIV-1 genome and, in this study, the SIV genome. They previously evaluated their ability to alter viral gene expression and replication in cultured cells and animal models. Additionally, their cell culture experiments confirmed that the editing tool cleaved integrated SIV DNA at the correct location. They also observed limited risk of potential harmful off-target effects.
CRISPR based editing
In this study, published in Nature Communications, researchers designed an adeno-associated virus 9 (AAV9)-CRISPR/Cas9 gene editing construct for eliminating proviral SIV DNA. They inoculated the construct intravenously into SIV-infected macaques – a well-accepted non-human primate model of HIV infection.
They found that this construct led to the broad distribution of editing molecules. Moreover, it resulted in the precise cleavage and removal of fragments of integrated proviral DNA from the genome of infected blood cells and tissues. Specifically, from viral reservoirs including lymph nodes, spleen, bone marrow and brain.
Overall, treatment with AAV9-CRISPR/Cas9 resulted in a reduction in the percentage of proviral DNA within the blood and tissues. These observations offer a promising step towards the elimination of HIV reservoirs in the clinic.
Dr. Andrew MacLean, co-corresponding author, stated:
“This is an important development in what we hope will be an end to HIV/AIDS.
The next step is to evaluate this treatment over a longer period of time to determine if we can achieve complete elimination of the virus, possibly even taking subjects off of ART.”
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