[ Back to EurekAlert! ]

PUBLIC RELEASE DATE:
18-Feb-2014

[ | E-mail ] Share Share

Contact: Jason Socrates Bardi
jbardi@aip.org
240-535-4954
American Institute of Physics

Unusual new HIV drug resistance mechanism revealed

Pittsburgh researchers show how therapy-induced resistance to 'NNRTI' drugs works at 58th Annual Biophysical Society Meeting in San Francisco

VIDEO: When it binds an inhibitor drug, HIV reverse transcriptase is forced into an open state that cannot transcribe RNA to DNA though a single amino acid mutation can make the...

Click here for more information.

WASHINGTON D.C. Feb. 18, 2014 -- For the more than one million people with HIV/AIDS in the United States (and the over 34 million people living with HIV/AIDS around the world), antiretroviral drugs such as efavirenz and other so-called non-nucleoside reverse transcriptase inhibitors (NNRTIs) in combination with other antiretrovirals can be a lifeline, because they slow the progress of viral infection, prolonging life. Unfortunately, studies have shown that these benefits themselves can be short-lived in the clinic: therapy with NNRTIs can lead to single (or "point") mutations in the HIV genetic code -- mutations that make the virus resistant to the drugs.

Researchers at the University of Pittsburgh School of Medicine now have a good idea why. In work to be presented at the 58th Annual Biophysical Society Meeting, which takes place in San Francisco from Feb. 15-19, cell biologist Sanford Leuba and his colleagues offer new insight into how NNRTIs function and how therapy-induced point mutations actually confer drug resistance.

NNRTIs work by blocking the action of an enzyme called reverse transcriptase, which HIV uses to convert its own genetic material (in the form of RNA) into single-stranded copies of DNA, which can then be inserted into the genome of the human cells they've infected. Once incorporated, this DNA instructs the host to create new copies of the virus, propagating the infection to new cells and over time attacking the immune system, which can lead to full-blown AIDS.

Using a number of imaging techniques and computer modeling, Leuba and his team showed that, normally, the binding of efavirenz results in the formation of a molecule-sized "salt bridge" that holds the reverse transcriptase in an open state when it is attached to the template it uses in making DNA copies. "The reverse transcriptase can still bind the template, but it continually slides," Leuba explained, "preventing the enzyme from polymerizing nucleotides. The virus cannot replicate."

The point mutations that cause resistance to efavirenz, the researchers found, prevent that salt bridge from forming, "allowing the reverse transcriptase to function normally," he says. "This type of inhibition, which does not involve drug-binding affinity, has not been described previously."

Based on the work, Leuba said, "We have ideas about how to begin designing a new generation of NNRTIs."

###

The presentation "A Gripping New Mechanism of Drug Resistance in HIV-1 Reverse Transcriptase" by Grant Schauer, Nic Sluis-Cremer and Sanford Leuba will be at 1:45 p.m. on Tuesday, February 18, 2014 in Hall D in San Francisco's Moscone Convention Center.

ABSTRACT: http://tinyurl.com/km59vnu

ABOUT THE MEETING

Each year, the Biophysical Society Annual Meeting brings together more than 7,000 researchers working in the multidisciplinary fields representing biophysics. With more than 4,200 poster presentations, over 200 exhibits, and more than 20 symposia, the BPS Annual Meeting is the largest meeting of biophysicists in the world. Despite its size, the meeting retains its small-meeting flavor through its subgroup symposia, platform sessions, social activities, and committee programs.

The 58th Annual Meeting will be held at the Moscone Convention Center, 747 Howard Street, San Francisco, California.

PRESS REGISTRATION

The Biophysical Society invites professional journalists, freelance science writers and public information officers to attend its Annual Meeting free of charge. For press registration, contact Alisha Yocum at ayocum@biophysics.org or Jason Bardi at 240-535-4954.

QUICK LINKS

Main Meeting Page: http://tinyurl.com/mfjh37p

Program Highlights: http://tinyurl.com/mosxrof

Abstracts Search: http://tinyurl.com/lbrearu

ABOUT THE SOCIETY

The Biophysical Society, founded in 1958, is a professional, scientific Society established to encourage development and dissemination of knowledge in biophysics. The Society promotes growth in this expanding field through its annual meeting, monthly journal, and committee and outreach activities. Its 9000 members are located throughout the U.S. and the world, where they teach and conduct research in colleges, universities, laboratories, government agencies, and industry. For more information on the Society, or the 2014 Annual Meeting, visit http://www.biophysics.org



[ Back to EurekAlert! ] [ | E-mail Share Share ]

 


AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.