'Shock and Kill' Approach Advances Towards HIV Cure

A newly-developed technique that detects rare cells that hide HIV and prevent treatment is advancing research for an HIV cure.

HIV reservoirs are cells and tissues that the virus uses to evade antiretroviral therapy (ART). Typically, HIV lives and replicates in CD4+ T lymphocytes. In the new study published in Cell Host & Microbe, however, researchers took a step forward in finding a cure for HIV/AIDS.

“We can wake up the virus and then find the rare cells that have been hiding it at very low numbers, a limit of 1 cell in a million,” said senior study author Daniel Kaufmann. “This is an unprecedented level of accuracy, which opens the door to individualized monitoring of HIV-positive patients and could facilitate the development of personalized treatments.”

For the study, researchers wanted to find a way to eliminate these leftover infected cells.

“CD+4 T lymphocyte populations are highly variable,” Kaufmann said. “To develop new targeted treatments to eliminate these residual infected cells, we need to find exactly where in the CD4 T lymphocyte population the virus hides. Our research has uncovered these HIV hiding places. We were able to identify and quantify the cells containing hidden virus and then test drugs to wake up HIV.”

The results of the study were a significant breakthrough, with the team developing an innovative technique that detects these reservoirs. The approach is 1000 times more accurate than any current technologies.

When the hiding places of the virus are discovered, the researchers can use a “shock and kill” strategy to eliminate the HIV in 2 stages: the HIV is first woken up from its dormant state in the cells, and then the virus becomes visible to either the immune system or drugs that can eliminate it.

During the study, researchers analyzed blood samples from 30 patients with HIV, both before patients started treatment and after they had received ART.

“We were able to detect the virus in CD4+ T lymphocytes in almost all of the patients we analyzed,” said first study author Amy Baxter.

Next, researchers tested 2 drugs called bryostatin and a derivative of ingenol, which were developed to fight cancer, but may also be used against HIV.

“While our studies were conducted in the laboratory, a clinical trial would involve using such drugs to wake up the virus while the patient continues taking ART to ensure that the reactivated virus cannot infect other cells,” Kaufmann said.

The results showed that the drugs woke up different populations of CD4+ T lymphocytes, which arose from different reservoirs. The ingenol derivative activated the population of central memory cells.

“These cells can live for years in patients, all the while hiding the virus. Therefore, it is particularly important to target these reservoirs,” Baxter said.

Initially, it appeared that the virus hides in similar places in different patients, however, researchers found large variability from 1 patient to another.

“We may have to adjust the treatment for individual patients, depending on the specific HIV hiding places in each case,” Kaufmann said. “To minimize the virus pools, we will have to assess patients and tailor the ‘shock and kill’ therapies to their profiles.”

The next steps the researchers are planning is to evaluate the efficacy of new drugs to awaken similar virus reservoirs in monkeys, and to locate where the virus is hidden. If this is well tolerated, then clinical trials will begin in a few years.