Gene Regulation May Overpower Hidden HIV Reserves

Overcoming HIV’s ability to lie dormant in the presence of antiretroviral therapy (ART) is the key to developing a cure for the virus; however, this goal remains elusive.

New research published in The Journal of Clinical Investigation suggests that an epigenetic mechanism that controls gene expression may draw HIV out of hiding and make it vulnerable to ART.

“We have been working on mechanisms that could be used to disrupt HIV latency,” said senior author Satya Dandekar, PhD. “The goal is to force the virus to be expressed so it is visible to the immune system and can be targeted through immuno-therapeutics. This is the first study to identify histone crotonylation as a driver for HIV transcription and de-crotonylation of histone as an epigenetic marker for HIV silencing.”

In the new study, the researchers focused on crotonylation in hopes that it could hold the key to curing HIV. This mechanism modifies the protein that packages DNA, which affects gene expression.

“Histone crotonylation regulates HIV latency,” said first author Guochun Jiang, PhD. “If we can modulate that, the virus can be more efficiently flushed out.”

To gain a more in-depth understanding of the crotonylation, the authors investigated the ACSS2 enzyme, which plays a role in fatty acid metabolism in the gut. This enzyme may be an important target, as HIV has been linked to impaired lipid metabolism, according to the study.

The researchers examined blood samples from HIV-positive patients and cell models of latency.

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When ACSS2 was activated, viral transcription manifold increased, according to the study. The authors also noted that this resulted in similarly encouraging results in patient samples.

“We examined well-characterized cell models of HIV latency and immune cells from HIV patients who had been undergoing antiretroviral therapy and had undetectable viral loads,” Dr Dandekar said. “In those samples, we were able to disrupt the HIV silencing by inducing histone crotonylation.”

Building on these results, the researchers treated the samples with an inhibitor of ACSS2. Treatment was found to lower detectable viral levels, which reinforces the role of decrotonylation in HIV latency, according to the study.

Interestingly, increasing histone crotonylation was found to work synergistically with other anti-HIV latency treatments, which suggests a combination therapy could help target latent cells, according to the study.

The authors are currently working to discover additional molecules that attack latency in order to formulate a stronger attack against HIV.

“We are looking for synergistic disruption, by combining histone crotonylation with other mechanisms to reactivate HIV,” Dr Dandekar said. “This research positions us to screen and identify small molecules, which can be optimized to carry out HIV modification.”