For the first time, scientists have determined how HIV is able to duck a commonly used drug.
Researchers from the University of Pittsburgh School of Medicine presented their findings today at the Biophysical Society annual meeting in San Francisco. Cell biologist Sanford Leuba and colleagues studied the molecular activity of efavirenz, an antiretroviral drug that is one of a class of drugs called non-nucleoside reverse transcriptase inhibitors, or NNRTIs. Efavirenz is sold under the brand name Sustiva, or Atripla when used in combination with another drug.
NNRTIs work by keeping HIV from piercing CD4+ “helper” cells and hijacking their genetic material to turn them into machines used for copying the virus. But the virus has found ways to adapt to NNRTIs and become resistant to them in some patients.
Leuber told Healthline that his team made the discovery by studying a “tour de force of expressions” previously found by their colleague Nicolas Sluis-Cremer. Sluis-Cremer is an internationally recognized expert on reverse transcription who also studies HIV drug resistance.
NNRTIs normally create a tiny “salt bridge” that keeps HIV from performing reverse transcription on cells. Reverse transcription is required for HIV to enter and corrupt the CD4+ cell with its genetic information. The salt bridge prevents HIV from fully grasping the cell, much like a hand that cannot close to fully clench an object.
Instead, the viral cell slides against the healthy cell, and this sliding keeps it from replicating. But Leuber and his colleagues now know that the sliding sometimes continues until the salt bridge eventually breaks, or is unable to form, allowing HIV to get inside the cell.
A 'Eureka' Moment
Leuber told Healthline there was “a screaming moment” when this mutation was first observed in the laboratory. “My interests are watching proteins move in real time on nucleic acid,” he said, adding that he did not know this could be done with HIV reverse transcription until now.
Dr. Daniel Kuritzkes, a professor of virology at Harvard University who also studies how HIV develops resistance to antiretroviral medications, told Healthline that Leuber's research is “interesting, but not earth-shattering.”
Kuritzkes said that the discovery has greater implications for the field of biochemistry than for advancing patient treatment. “But the truth is that the more we understand about the mechanisms of action for drug resistance, the better we may be able to design molecules that can overcome those mechanisms," he said.
"What people would ideally want are molecules that anticipate the mechanism of resistance and have patterns of escape.”
One in Six Carry Drug Resistant HIV Strain
More than 16 percent of Americans with HIV carry a strain of the virus that is resistant to certain drugs, according to research presented in March 2013 at the Conference on Retroviruses and Opportunistic Infections in Atlanta, Ga. In half of those cases, the virus is resistant to NNRTIs.
Although the majority of patients taking antiretroviral drugs do well, “for a significant subgroup of patients who have trouble taking their medications regularly, these people can get into trouble with resistance,” Kuritzkes said. “Resistance to non-nucleosides is a problem.”