HIV Drug Potent Against Drug Resistance in Preclinical Testing

Through advancements in preventive treatments and antiretroviral therapy (ART), patients with HIV are able to live longer lives and the virus has largely become a manageable, chronic condition.

However, drug-resistant strains of HIV threaten to undo the significant progress that has been achieved. Additionally, patients may struggle to remain adherent to daily therapy, especially if they experience side effects.

Results from a preclinical trial published by eLife suggest that an investigational protease inhibitor may be a crucial tool in the fight against multi-drug resistant HIV strains.

In cell culture experiments, the authors assessed the dose of GRL-142 needed to suppress HIV replication.

The investigators discovered that the concentration of the experimental drug was half as much as needed for 9 approved protease inhibitors to achieve suppression, according to the study.

Importantly, GRL-142 was observed to be effective at small concentrations, up to 1 billion-fold lower concentrations than current treatments, according to the study.

The authors said these results suggest that GRL-142 may prevent the emergence of drug-resistant strains of HIV.

To gain a better understanding of the drug’s mechanisms of action, the researchers used X-ray crystallography to image the interaction between GRL-142 and the HIV protease. They discovered that the experimental drug works similarly to the antiviral darunavir, but forms stronger bonds to HIV protease and its subunits, according to the study.

The authors noted that a majority of ART agents are unable to cross the blood-brain barrier, which allows HIV to replicate uninhibited in the brain. This phenomenon may lead to HIV-associated neurocognitive disorders (HAND), which can cause tremors and memory loss, according to the authors.

When rat models were administered GRL-142, drug concentration in the brain achieved levels 114-fold greater than needed to completely block HIV replication, according to the study. These findings suggest that the drug shows promise to inhibit HIV from infecting and replicating unchecked in the brain.

The authors concluded that GRL-142 may be a promising drug for HIV that could prevent drug-resistance and HAND. GRL-142 is currently being tested in primates, with the hope of transitioning to human clinical trials, according to the study.