Kick And Kill Approach Targets Latent HIV

Current anti-AIDS drugs are highly effective at making HIV undetectable and allowing people with the virus to live longer, healthier lives. The treatments, a class of medications called antiretroviral therapy, also greatly reduce the chance of transmission from person to person.

But the medications do not actually rid the body of the virus, which has the ability to elude medications by lying dormant in cells called CD4+ T cells, which signal another type of T cell, the CD8, to destroy HIV-infected cells.

When a person with HIV stops treatment, the virus emerges and replicates in the body, weakening the immune system and raising the likelihood of opportunistic infections or cancers that can sicken or kill the patient.

Researchers have been looking for ways to eliminate the “reservoirs” where the virus hides, and researchers from UCLA, Stanford University and the National Institutes of Health may have developed a solution. Their approach involves sending an agent to “wake up” the dormant virus, which causes it to begin replicating so that either the immune system or the virus itself would kill the cell harbouring HIV.

Scientists call the technique “kick and kill.”

Activating Latent HIV

Destroying the reservoir cells could rid some or all of the HIV virus from people who are infected. And although the scientists’ approach has not been tested in humans yet, a synthetic molecule they developed has been effective at kicking and killing HIV in lab animals, according to a new study.

“The latent HIV reservoir is very stable and can reactivate virus replication if a patient stops taking antiretroviral drugs for any reason. Our study suggests that there may be means of activating latent virus in the body while the patient is on antiretroviral drugs to prevent the virus from spreading, and that this may eliminate at least some of the latent reservoir,”

said lead author Matthew Marsden, an assistant professor of medicine in the division of hematology oncology at the David Geffen School of Medicine at UCLA.

To test the approach, the researchers gave antiretroviral drugs to mice that had been infected with HIV, and then administered a synthetic compound called SUW133, which was developed at Stanford, to activate the mice’s dormant HIV. Up to 25 percent of the previously dormant cells that began expressing HIV died within 24 hours of activation.

Activation of HIV from latency in patient-derived cells

Activation of HIV from latency in patient-derived cells.
Credit: Matthew D. Marsden, et al.

With further development, the technique could lower the viral reservoir enough for people with HIV to be able to discontinue their anti-viral therapy, Marsden said.

Synthetic Bryostatin Analog

SUW133 is based on bryostatin 1, a natural compound extracted from a marine animal called Bugula neritina. The research determined that the new compound is less toxic than the naturally occurring version.

“The findings are significant because several previous attempts to activate latent virus have had only limited success. Most studies showed weak activation of the virus, or severe toxicity, with little effect on the reservoir,”

said senior author Jerome Zack, professor and chair of the UCLA department of microbiology, immunology and molecular genetics at the Geffen School, and director of the UCLA Center for AIDS Research.

Marsden said results in mice will not necessarily translate to humans. In further studies, the scientists plan to learn how to make SUW133’s less toxic, and to evaluate its effectiveness in larger animals, before it could be tested in humans.

This work was supported by the National Institute of Health, the Bill and Melinda Gates Foundation, the James B. Pendleton Charitable Trust, and the UCLA Center for AIDS Research.

Marsden MD, Loy BA, Wu X, Ramirez CM, Schrier AJ, Murray D, et al.
In vivo activation of latent HIV with a synthetic bryostatin analog effects both latent cell “kick” and “kill” in strategy for virus eradication
PLoS Pathog 13(9): e1006575. https://doi.org/10.1371/journal.ppat.1006575

Top Image: CDC, A. Harrison and Dr. P. Feorino