An emerging cancer treatment also helps prevent cells from turning into viral factories by interfering with HIV infection processes inside the cell, according to a recent Northwestern Medicine study published in Cell Reports.
While older treatments using this strategy — called mTOR inhibitors — have been tested in a small number of patients with HIV, this new class of drugs may be more effective at slowing the spread of HIV within the body, according to Richard D’Aquila, MD, the Howard Taylor Ricketts, MD, Professor of Medicine and senior author of the study.
“We showed that there are several ways in which mTOR activity is required within the cell, both to make building blocks of DNA and the molecules needed to move HIV through the cell,” said D’Aquila, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
mTOR is a kind of enzyme known as a kinase, and is important for cell growth and metabolism in CD4 T-cells. mTOR inhibitors are antiretroviral drugs that work in part to prevent HIV from entering T-cells by disabling certain receptors on the cell surface. However, less is known about how these inhibitors affect HIV operations within the cell, according to D’Aquila.
Further, mTOR inhibitors currently on the market inhibit just one of the two mTOR complexes, mTORC1. New inhibitors in development inhibit the second complex, mTORC2, as well as mTORC1. These new inhibitors have been shown to be more effective in mouse models and some human cells.
In the current study, D’Aquila and his collaborators examined the effects of an inhibitor of both mTOR complexes in human CD4 T-cells. They used a modified strain of HIV that can enter cells independently of the surface receptors in order to analyze the internal workings of the cell, rather than mTOR’s impact on the surface.
The investigators found that mTOR inhibitors prevented accumulation of fuel-like glucose in the cell, which is used by the cell and required for HIV to copy its RNA into DNA and eventually make more copies of the virus.
In addition, they found that mTORC2 inhibition slows production of another cellular building block: acetyl-CoA. This substance is used to create microtubules that transport products of HIV into the nucleus where they establish infection and begin to replicate — a process that was blocked by the inhibitor of both mTOR complexes.
“This is one reason why we think the new inhibitors work better,” said D’Aquila, who is also director of the Northwestern University Clinical and Translational Sciences (NUCATS) Institute and senior associate dean for clinical and translational research.
Interestingly, while HIV used glucose as fuel in activated CD4 T-cells, this fuel is not available to HIV in resting CD4 T-cells, according to Harry Taylor, PhD, assistant professor of Microbiology and Immunology at Upstate Medical University in New York, formerly a research assistant professor in the D’Aquila laboratory, and lead author of the study.
“This answers a long-standing question in the HIV field about what drives HIV infection in activated CD4 T cells, its preferred target cell,” Taylor said.
Because acetyl-CoA is also used in later steps of HIV infection — beyond when viral RNA is brought to the nucleus — inhibitors of both mTOR complexes could possibly keep the virus latent. A therapy that could prevent latent viruses from reactivating would give patients some breathing room on anti-retroviral medication, according to D’Aquila.
“Patients have to take them every day for the rest of their lives and the medication can be quite expensive,” D’Aquila said. “With something like this as a brief added treatment before stopping everything, maybe we could have sustained remission for weeks or months without keeping people on their current regimen.”
In the future, D’Aquila and his collaborators hope to examine in more detail how mTOR regulates HIV infection after viral RNA is transported to the nucleus, hoping to find that mTOR inhibitors could tamp down viral activity there, too.
“That’s the next step, that’s what we want to look at,” D’Aquila said.
This work was supported by National Institutes of Health (NIH) grant P01 AI 131346, a Northwestern Medicine Catalyst Award and a Developmental Core Pilot Project award from the Third Coast Center for AIDS Research (CFAR), an NIH-funded center (P30 AI117943).