HIV’s sweet tooth may be its downfall

"It's a monster that invades the cell and says 'feed me!'" says Harry Taylor. (Credit: mateoutah/Flickr)

Once HIV invades an activated immune cell, it needs sugar and nutrients from the cell to fuel its wild growth. Now scientists say that voracious sweet tooth also may be its Achilles’ heel.

Scientists discovered the switch that turns on the immune cell’s abundant sugar and nutrient pipeline. Then they blocked the switch with an experimental compound, shutting down the pipeline and starving HIV to death. The virus was unable to replicate in human cells in vitro.

Researchers say the findings may have applications in treating cancer, which also has an immense appetite for sugar and other nutrients.

HIV cocktail

“This compound can be the precursor for something that can be used in the future as part of a cocktail to treat HIV that improves on the effective medicines we have today,” says Harry Taylor, research assistant professor in medicine at Northwestern University.

“It’s essential to find new ways to block HIV growth, because the virus is constantly mutating,” says Taylor. “A drug targeting HIV that works today may be less effective a few years down the road, because HIV can mutate itself to evade the drug.”

HIV needs to grow in a type of immune cell (CD4+ T cell) that is active, meaning it is already responding to pathogens in the blood. Activation increases the T cell’s supplies of sugar and other critical nutrients.

Until now, no one knew the first step that signaled a newly activated T cell to stock up on sugar and other nutrients. Those nutrients become the building blocks of genetic material the cell and the virus need to grow.

T cell’s pantry

For the study, published in the journal PLOS Pathogens, scientists first figured out that the first step in stocking the T cell’s pantry involved turning on a cell component called phospholipase D1 (PLD1). Then they used an experimental compound to block PLD1 and shut down the pipeline.

This is the first known example of scientists targeting the virus’s ability to pilfer the cell’s pantry to stop its growth. A related approach was tried in the 1990s but the drugs used sometimes killed healthy cells and had serious side effects in HIV patients.

The new approach—a nontoxic way to block HIV access to the cell’s “pantry”—has additional benefits beyond the initial goal of preventing HIV from reproducing, researchers say.

The compound also slowed the proliferation of the abnormally activated immune cells. Current HIV medications stop HIV growth but do not affect the abnormal excess activation and growth of immune cells triggered by HIV.

‘Feed me!’

The excess immune cell growth is believed to contribute to the life-long persistence of HIV and leads to excess inflammation that causes premature organ damage in HIV patients—even when the virus is suppressed by current medicines.

“Perhaps this new approach, which slows the growth of the immune cells, could reduce the dangerous inflammation and thwart the life-long persistence of HIV,” Taylor says.

When HIV enters the bloodstream, it searches out active CD4+ T cells, the commanders-in-chief of the immune system. These active cells are already responding to other pathogens or allergens in the blood and are guzzling glucose and amino acids from the blood, which they need to churn out the building blocks of DNA.

The cells’ factories are at full throttle, making these building blocks to produce an army of soldiers to fight that cold that has just started to give you a sore throat or the chills.

When HIV finds an active CD4+ T cell, it hijacks the cell’s glucose supply and factory to build millions of copies of itself and invade other cells.

“It’s a monster that invades the cell and says ‘feed me!’ ” Taylor says. “It usurps the entire production line.”

Cancer cells crave sugar, too

The idea to test this compound for HIV evolved from Taylor’s relationship with chemists at Vanderbilt University, where he was on faculty before joining Northwestern in 2012.

Taylor knew his Vanderbilt colleagues had identified a compound in their massive screening for potential drugs that block the growth of breast cancer cells. The compound stopped breast cancer cells from spreading by blocking PLD1.

Researchers wondered if blocking this same enzyme in the CD4+ T cell would cut off HIV’s use of the cell’s nutrient supply and slow the invading HIV.

And that’s exactly what the new study shows. In vitro, the compound shut off the glucose and other nutrients and prevented HIV from having enough building blocks of DNA to make the genetic material it needed to reproduce.


Now, Taylor wants to identify even more compounds for development into future medicines that will limit re-stocking of the cell’s pantry to starve HIV—without harming cells.

“This discovery opens new avenues for further research to solve today’s persisting problems in treating HIV infection: avoiding virus resistance to medicines, decreasing the inflammation that leads to premature aging, and maybe even one day being able to cure HIV infection,” says Richard D’Aquila, director of Northwestern’s HIV Translational Research Center and a professor of medicine at Feinberg.

Craig W. Lindsley and H. Alex Brown from Vanderbilt collaborated on the study.

Northwestern Medicine’s HIV Translational Research Center, the National Institute of Mental Health, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center for Research Resources, and the National Cancer Institute of the National Institutes of Health supported the work.

Source: Northwestern University