Antiretroviral therapy (ART) is a very effective treatment for patients living with HIV. However, infected cells can become latent and persist as viral reservoirs that could rekindle HIV infection if antiretroviral therapy is stopped.
Some of these reservoirs have very long half-lives and their complete eradication could take more than 60 years. Thus, eliminating these cellular reservoirs of HIV is both a challenge and a priority.
A common strategy is to administer molecules that reactivate latent viruses while a patient is on HIV treatment, allowing the immune system to recognize and attack these once-dormant cells. Different classes of latency reversal agents (LRAs) have varying potencies ex-vivo. New research, published in eBioMedicineexamined DNA methylation, a chemical modification of DNA that maintains HIV-1 persistence but is not well understood.
Researchers have shown that the cellular protein UHRF1 helps maintain HIV latency, promoting DNA methylation in the viral genome. By inhibiting UHRF1, through molecular or pharmacological manipulation, the researchers reactivated the cellular reservoirs of HIV. No longer latent, these HIV cells have been primed to be detected and destroyed by the immune system.
This study used epigenetic interrogation methods, such as electrophoretic mobility shift assays, chromatin immunoprecipitation, and the Infinium Network, in models of HIV infection. Investigators measured extracellular staining of cell surface receptors and intracellular metabolic activity of drug-treated cells.
Anti-UHRF1 molecules have already been used in cancer therapies to awaken latent virus reservoirs. A known UHRF1 inhibitor, epigallocatechin-3-gallate (EGCG), can be safely administered to humans to trigger viral expression ex-vivo.
Using cells isolated from 22 Belgian patients, the researchers demonstrated for the first time the ability of EGCG to reactivate HIV reservoirs. Simultaneously, the antiviral properties of EGCG limit the spread of infection. Pharmacological inhibition of UHRF1 in ex-vivo HIV cells induced a potent reactivation of latent viral reservoirs. “These results are encouraging for the development of innovative anti-HIV therapies based on UHRF1 inhibition,” conclude the study authors.