A "Fossil" Virus Involved In AIDS Drug Resistance?

December 04, 1998

Genetic remnants of an ancient virus, incorporated into every human's DNA, may be responsible for some resistance to anti-AIDS drugs, according to researchers working for Science Applications International Corporation (SAIC), a sub-contractor to the National Cancer Institute (NCI) in Frederick, Md. Noting it's a radical idea, the scientists suggest those viral genes may create an enzyme that assists the AIDS virus, HIV-1, when its own protease is rendered ineffective by current drugs.

Details of this research, the first isolation of a fully active protease from an endogenous virus gene, appear in the December 8 edition of the peer-reviewed journal Biochemistry, published by the American Chemical Society, the world's largest scientific society.

Every human has 30-50 incomplete copies of genetic instructions for making a now extinct virus, called human endogenous retrovirus type K (HERV-K). Why they have been preserved in humans is unclear and no infectious viral particles have been discovered to date. But the gene portions can apparently make viral parts.

SAIC scientist Eric Towler, Ph.D. says, "HERV-K protease may be complementing the activity of HIV protease during drug treatment in some way, and that's what we need to find out."

A protease is like a pair of protein scissors. HIV-1's genetic machinery churns out long protein chains from which its protease makes specific cuts to create functional parts. Protease inhibitors block the cutting. But, even in the presence of multiple inhibitors, HIV-1 often seems to find a way to get the job done. This is due, at least in part, to the virus developing mutations that make the protease resistant to multiple drugs.

"Many of the sequence changes in HERV-K protease are at the same sites where drug resistant mutations for HIV protease have been observed," says SAIC structural biochemist Sergei Gulnik, Ph.D.

It is possible that resistance is not due entirely to mutations, say the scientists. Maybe the HERV-K protease, made within a patient's own body, is taking over for some of the HIV-1 protease when it is inactivated. "We tried to determine whether any of the inhibitors that are approved or are in clinical trials can inhibit the HERV-K protease," adds Gulnik, "and we found that it is highly resistant to most of these inhibitors."

In the Biochemistry report, the scientists also say laboratory experiments show that HERV-K protease cuts at a proper site within an HIV-1 polyprotein. But they add that follow-up studies will be needed to determine whether the HERV-K protease actually lends a helping hand to HIV-1 in AIDS patients. If so, future AIDS treatments may need to be developed for yet another target. "It's a radical theory," says Towler. "The hypothesis is a little bit on the fringe, but we have had some surprising results that support it."

This research is part of an ongoing effort to establish the underlying basis of drug resistance mechanisms for HIV-1 led by Dr. John W. Erickson, Director of the SAIC/NCI Structural Biochemistry Program, and was a collaborative effort that included scientists at the Institute Medizinische Mikrobiologie und Hygiene, Universitatskliniken des Saarlandes, Homburg, Germany.
A nonprofit organization with a membership of more than 155,000 chemists and chemical engineers, the American Chemical Society publishes scientific journals and databases, convenes major research conferences, and provides educational, science policy and career programs in chemistry. Its main offices are in Washington, D.C., and Columbus, Ohio.

American Chemical Society

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