Researchers have discovered how a certain cellular pathway regulates the resting state, or latency, of HIV-infected immune cells that make up much of the viral reservoir. This new understanding of how HIV latency works may help in developing new cure methods.

The branch of the HIV cure research field devoted to the so-called “shock and kill” approach has been beset by a series of disappointments in recent years.

These methods use what are known as latency-reversing agents to get HIV-infected immune cells that are not replicating—which means they stay under the radar of standard antiretroviral treatment, which works only against replicating cells—to reactivate and once more begin to churn out new copies of the virus.

In a successful shock-and-kill therapy, a “kill” agent would then be used to kill off these newly activated cells.

But the latency-reversing agents studied so far have proved disappointing.

Searching for better ways to reverse HIV latency, researchers at the Gladstone Institutes in San Francisco studied a protein known as FOXO1. This protein helps keep T cells from being activated when the body doesn’t need them.

“Antiretrovirals have been hugely successful for managing HIV, but latency is the final unsolved part of the equation,” senior study author Melanie Ott, MD, PhD, director of the Gladstone Institute of Virology, said in a press release. “We hope the new pathway we uncovered can be exploited to activate the latent virus and fully eliminate it.”

Publishing their findings in Nature Microbiology, the investigators found that treating latently HIV-infected T cells with a drug that inhibits FOXO1 reactivated HIV in both a laboratory setting and in people living with the virus.

Seeking to better understand the pathways that govern this phenomenon, the investigators conducted further experiments in cell lines and cells from HIV-positive individuals. They found that inhibiting FOXO1 reduces the expression of genes that help cells break down components they don’t need. Then, as unneeded proteins accumulate in the cells, this causes what’s known as endoplasmic reticulum (ER) stress to the cell. In turn, the ER stress activates a pair of proteins that spur latently HIV-infected cells to reactivate.

These findings suggest that activating ER stress could be a means of reactivating HIV in a shock and kill approach. In keeping with the prevailing wisdom in the HIV cure research field these days, this therapy will probably need to be used in combination with other approaches to be effective.

In fact, the study authors have already found that combining a FOXO1 inhibitor with another latency-reversing drug had a synergistic effect on HIV reactivation.

Perhaps even more intriguing is the fact that inhibiting FOXO1, the investigators found, could prevent HIV from going into a latent state in the first place. So it’s possible such a therapy could be used to help minimize the establishment of the viral reservoir in people with HIV.

Researchers, including Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), have suggested, after all, that those with smaller reservoirs will be the most likely to respond well to HIV cure therapies.

To read a press release about the study, click here.

To read the study abstract, click here.