Drug Resistance Looms in African HIV Strains

A study has shown that genetic differences between the subtypes of HIV prevalent in Africa and the subtype dominant in the United States and Western Europe appear to amplify the effects of protease-inhibitor-resistant mutations in the African strains of HIV. The study appeared in the July 9, 2002, issue of Biochemistry.

"What we observed at the molecular level might have negative implications for the long-term efficacy of antiviral therapies in patients infected with the African subtypes,” said Dr. Ernesto Freire, professor of biology at Johns Hopkins University (Baltimore, MD, USA). "If this is the case, the need for second-generation therapies acquires renewed urgency.”

The principal drugs currently used to treat HIV inhibit two key enzymes in the life cycle of the virus, protease and reverse transcriptase. Mutations in these enzymes can affect the ability of the inhibitors to bind to them, leading to drug resistance.

In the current study, a mutation commonly found in drug-resistant forms of HIV-B, the strain of HIV prevalent in Western Europe and North America, was inserted into the proteases of the African HIV strain. Analyses showed that the new, drug-resistant HIV-A and HIV-C proteases were up to 1,000 times more active despite the presence of four common protease inhibitor drugs.
"The genetic variations that exist in the protease of these African strains are not sufficient to cause drug resistance by themselves,” Professor Freire said, "but they amplify the effects of drug-resistant mutations and therefore may lead to a faster long-term failure of the therapy.”

Genetic variation has been a key contributor to the spread of HIV, but drug development work has been focused almost exclusively on HIV-B, which is dominant in some regions but a minority in the worldwide epidemic. Approximately 70% of existing AIDS cases are HIV-A and HIV-C cases in Africa, and these subtypes can vary genetically from HIV-B by as much as 30%. Professor Freire believes that these factors, together with his research results, make the inclusion of HIV-A and HIV-C in AIDS drug development efforts a priority.




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