New Tool Reveals Mutations That Cause HIV-drug Resistance

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A researcher at the National Institute for Mathematical and Biological Synthesis (NIMBioS) at the University of Tennessee, Knoxville, has uncovered one of the reasons why a popular HIV drug is short on effectiveness.

Protease inhibitor drugs are one of the major weapons in the fight against HIV, the virus that causes AIDS, but their effectiveness is limited as the virus mutates and develops resistance to the drugs over time.

The main reason for the short-term effectiveness of the drug has to do with the evolution of the drug within the body, says Yi Mao, a postdoctoral fellow at NIMBioS.

In his new study, published in the journal BMC Structural Biology, Mao used a mathematical modeling technique called elastic network modeling, to examine the physical properties and interactions of the proteins. The model reveals where mutations occur during the evolution of the HIV-virus proteins and how these mutations help the virus survive.

“With this kind of knowledge, better strategies for designing anti-HIV drugs could be developed,” Mao said.

HIV kills the body’s immune system cells, called CD4 cells. Once the number of CD4 cells dips below 200, an HIV patient enters the last stage of his or her disease: Acquired Immune Deficiency Syndrome, or AIDS. The first cases of AIDS were reported thirty years ago. Since then, more than sicty million people have been infected with HIV, and more than thirty million people have died from AIDS. Today an estimated thirty-four million people worldwide are living with HIV – 1.2 million in the US.

First discovered in 1995, protease inhibitor drugs have dramatically reduced the number of AIDS deaths. Taken in combination with two other drugs, protease inhibitors work by halting the action of the protease enzyme—a protein produced by HIV that is necessary for replication of the virus. However, almost half of HIV patients who initially respond to treatment with protease inhibitors develop drug-resistant strains of the disease and stop responding to treatment within eight to ten months.

Currently there are nine FDA-approved protease inhibitors, and twenty-one drug-resistant mutations.

NIMBioS brings together researchers from around the world to collaborate across disciplinary boundaries to investigate solutions to basic and applied problems in the life sciences. NIMBioS is sponsored by the National Science Foundation, the US Department of Homeland Security, and the US Department of Agriculture, with additional support from UT Knoxville.

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