New Screening Method Identifies Chemicals That Can Keep HIV Latent

Investigators may have found a way to locate chemicals capable of suppressing HIV into its dormant state, according to a study published in the Proceedings of the National Academy of Sciences.

The virus spreads by infecting cells and then exploiting those cells to make copies of the virus. Without making copies in this manner, the virus is forced to remain dormant, a term called latency.

"The current drug treatments block healthy cells from becoming infected by the virus," said Yiyang Lu, a PhD student in the Dar lab at the University of Illinois Urbana-Champaign, in a press release. "The latent reservoir poses a bigger problem because it can start producing the virus at any time. Consequently, patients have to remain on antiretroviral therapy all their lives to prevent a viral rebound."

Currently, the 2 available drug treatment strategies are to shock-and-kill or block-and-lock the virus. In the shock-and-kill treatment method, reactivated cells are killed, and then a second combination treatment is used to prevent the virus from spreading to other cells. In the block-and-lock approach, the virus is forced into a latent state so that it does not reactivate again.

In the first approach, the problem has been that there remain leftover HIV reservoirs following treatment, causing patients to need to continue to take drugs to keep them latent. In the second approach, the problem for providers has been that there are not currently many drugs on the market accomplishing this approach.

The investigators in the new study were focused on addressing the problem present in the second approach: the lack of drugs available. They noted that since the virus’s transition from latency is random, a measurement of gene expression fluctuation could provide additional valuable information.

"Commercial drug screens usually look at mean gene expression. Instead, we used a drug screen that looks at fluctuations in gene expression. Our screen allowed us to therefore find more compounds that could have been overlooked," Lu said in the press release.

Using a T cell population that had been infected by the virus, or an HIV reservoir, the investigators implemented a time-series drug screening that imaged the cells at 15-minute intervals for 48 hours. This method allowed the investigators to test more than 1800 compounds and assess noise maps to identify which drugs can modulate the gene expression.

Using this method, the investigators found 5 new latency-promoting chemicals. Based on this finding, the investigators also noted that similar screens could be adapted to study other systems that exhibit gene expression fluctuation, such as cancer. Currently, the investigators are assessing further how the 5 novel drugs are specifically able to suppress viral reactivation.

"We implemented a time-series drug screening approach that are less commonly used in other labs," said Roy Dar, PhD, an assistant professor of bioengineering at Illinois and faculty member of the Carl R. Woese Institute for Genomic Biology, in the press release. "We want to test if these drugs have off-target effects in terms of how many other genes they affect in the host cells. We also want to test these drugs in patient samples to see whether these drugs suppress HIV in them."

REFERENCE

Researchers hunt for drugs that keep HIV latent. Champaign, IL: Carl R. Woese Institute for Genomic Biology; March 23, 2021. https://www.eurekalert.org/pub_releases/2021-03/crwi-rhf032321.php. Accessed March 25, 2021.