HIV thrives when it can raid the sugar pantry that is an activated T cell. In fact, HIV is so dependent on its host’s abundant supply of glucose and other nutrients that the pilfering pathogen languishes if the T cell merely idles. A less-than-active T cell slows the flow of essential nutrients, starving the always-voracious HIV.
If a means of keeping T cells relatively inactive could be found, it would be possible to suppress HIV. To date, however, attempts to inhibit T cell activation have proved to be toxic. A more gentle approach, however, could interfere more subtly with the T cell’s internal signaling, essentially passing the word to revoke HIV’s meal ticket.
This gentler, but not kinder, approach was explored by researchers at Northwestern Medicine and Vanderbilt University. These researchers figure out that the first step in stocking the T cell’s pantry involved turning on a cell component called phospholipase D1 (PLD1). When the researchers blocked PLD1 in a series of in vitro experiments, they were able to suppress HIV replication.
The researchers published their findings May 28 in PLOS Pathogens, in an article entitled, “Phospholipase D1 Couples CD4+ T Cell Activation to c-Myc-Dependent Deoxyribonucleotide Pool Expansion and HIV-1 Replication.”
“[PLD1] links T cell activation signals to increased HIV-1 permissivity by triggering a c-Myc-dependent transcriptional program that coordinates glucose uptake and nucleotide biosynthesis,” wrote the authors. “Decreasing PLD1 activity pharmacologically or by RNA interference diminished c-Myc-dependent expression during T cell activation at the RNA and protein levels.”
The authors also provided details about a small molecule they used to accomplish PLD1 inhibition, which instigated a chain of events that ultimately thwarted efficient HIV reverse transcription. They added that their work has potential to augment current therapeutics for HIV.
“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,” said the study’s corresponding author, Harry Taylor, Ph.D., research assistant professor in medicine at Northwestern University Feinberg School of Medicine.
“It's essential to find new ways to block HIV growth, because the virus is constantly mutating,” added Dr. Taylor, also a scientist at Northwestern Medicine's HIV Translational Research Center. “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.”
The approach has additional benefits beyond the initial goal of preventing HIV from reproducing.
The compound also slowed the proliferation of the abnormally activated immune cells, the study found. Current HIV medications stop HIV growth but do not affect the abnormal excess activation and growth of immune cells triggered by HIV.
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,” Dr. Taylor said.
The authors of the PLOS Pathogen article also speculated that blocking PLD1 could be effective against cancer. In fact, the PLD1 inhibitor they evaluated in the current study was originally identified in a screening effort meant to find drugs against breast cancer. “Further development of PLD inhibitors holds promise as a potential therapeutic for viral infections that require host nucleotide pools for replication as well as cancers,” the authors concluded, “although the roles of PA production, whether biophysical, transcriptional, or as a signaling molecule, in these therapeutic interventions have yet to be fully elucidated.”