Journal News

JBC: When HIV drugs don’t cooperate

Sasha Mushegian
March 01, 2018

The term “synergy” has gained a reputation as an overused buzzword, but it has a quantifiable definition in pharmacology. Two drugs are considered synergistic if their effectiveness when used together is greater than the sum of their effects alone. That is, a drug that is synergistic with another doesn’t just perform a beneficial function itself but makes the second drug perform its function better.

Researchers at Thomas Jefferson University studying combinations of drugs against HIV have discovered why some drugs sometimes act synergistically but sometimes do not. The paper describing their research was published in the Journal of Biological Chemistry.

Second-line HIV drugs, used after first-line treatments have failed, target several steps in the process by which the virus enters human T cells. Because of the particular steps and proteins they target, two types of these drugs, called co-receptor antagonists and fusion inhibitors, are expected to be synergistic. But multiple previous studies have yielded contradictory results: sometimes these drug classes were indeed strongly synergistic, but sometimes they displayed no synergy at all.

Co-receptor antagonists like maraviroc (marketed under the brand name Selzentry) bind to receptors on host cells known as co-receptors. Fusion inhibitors like enfuvirtide (marketed as Fuzeon) bind to a viral protein called gp41 when it’s in a particular transitional phase. To understand why these drugs don’t always synergize as expected — and to gain a better understanding of the steps of the HIV infection process — associate professor of biochemistry and molecular biology Michael Root and his then-graduate student Koree Ahn applied various doses of maraviroc and enfuvirtide to cells and viruses with slightly different genetic sequences.

“We found that many different factors are important for (determining) whether there’s a synergistic interaction between these two classes of inhibitors or not,” Ahn said.

The first factor was the strength of the binding between enfuvirtide and gp41, which could vary depending on mutations in the viral gene that encodes gp41. If the sequence of the gp41 protein was such that enfuvirtide bound to it very tightly, then enfuvirtide and maraviroc acted synergistically. But the weaker the binding, the weaker the synergy between the two drugs.

This finding implies that when virus proteins evolve to avoid binding drugs, it doesn’t affect only the efficacy of the drug in question; it also affects how much its effects are boosted by other drugs. This is bad news for patients, because adding synergistic drugs to a treatment regimen is thought to be a way to combat loss of drug efficacy.

The second factor affecting synergy was the density of co-receptors on host cells, which can vary significantly among patients. “Some (patients) might have very high levels of (co-receptors) on their T-lymphocytes, and those patients would see robust synergy between these two classes of drugs,” Root said. “Another individual might have lower levels of co-receptors on the cell surface, and therefore not have as robust synergy, or none at all.”

Together, these results suggest that variations in viruses and in patients need to be considered when predicting the efficacy of drug combinations, including newly developed co-receptor antagonists and fusion inhibitors. The paper by Ahn and Root suggests mathematical models for doing just that.

“You need to use these (drugs) with care,” Root said. “Drug resistance can emerge with either one, and when resistance emerges you lose that extra benefit of synergy.”

Sasha Mushegian

Sasha Mushegian is a postdoctoral fellow at Georgetown University. Follow her on Twitter.

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in Science

Science highlights or most popular articles

Gut microbiome shaped by dietary sphingolipids
Journal News

Gut microbiome shaped by dietary sphingolipids

September 22, 2020

A new tracing method described in the Journal of Lipid Research offers clues on how a macronutrient interacts with the microbes that live inside us.

From the journals: JBC
Journal News

From the journals: JBC

September 21, 2020

Proteases that fire up the flu. A sulfate pocket to take out MRSA. Proteins that prompt cancer protrusions. Read about recent papers on these topics and more.

AeroNabs promise powerful, inhalable protection against COVID-19
News

AeroNabs promise powerful, inhalable protection against COVID-19

September 20, 2020

As the world awaits vaccines to bring the COVID-19 pandemic under control, UC San Francisco scientists have devised a novel approach to halting the spread of SARS-CoV-2, the virus that causes the disease.

Keeping bone and muscle strong on the ISS
News

Keeping bone and muscle strong on the ISS

September 19, 2020

Researchers helped mice stay mighty with an experiment to counter the effects of microgravity. The gene treatment might also enhance muscle and bone health on Earth — and in humans.

Understanding the impact of Type 1 diabetes susceptibility genes
Research Spotlight

Understanding the impact of Type 1 diabetes susceptibility genes

September 17, 2020

Starting in eighth grade, a series of mentors who saw something special in Sharifa Love–Rutledge helped her stay on the path to being a researcher — and becoming a mentor to others.

Re-creating coagulation in a lab
Journal News

Re-creating coagulation in a lab

September 15, 2020

Threatened arthropods are in the crossfire of medical and conservation efforts, but new research could benefit horseshoe crabs and humans alike.