African HIV strains appear more resistant to current therapies

July 03, 2002

Of the 40 million people infected worldwide with HIV, more than 70 percent live in Africa. Yet a new study suggests a key component in current therapies could be less effective on African forms of the virus. The findings are reported in the July 9 print issue of Biochemistry, a peer-reviewed journal of the American Chemical Society, the world's largest scientific society.

"Although clinical studies are still very limited, early reports in the medical literature have suggested a poorer long-term response to antiviral therapies in African patients, despite a similar initial response," said Ernesto Freire, Ph.D., professor of biology and biophysics at Johns Hopkins University and lead author of the paper.

One proposed explanation for the response has been patients' inability to adhere to the strict regimen required by antiretroviral drugs. But the new studies also suggest a molecular basis might be present.

HIV's shape-shifting nature has helped it reach epidemic proportions. The virus constantly morphs, causing drug resistance and geographical variations. For example, the HIV-B subtype predominates in Western Europe and the United States, while genetically different strains -- HIV-A and HIV-C -- occur mostly in Africa. Currently available therapies have been designed specifically for the B subtype, Freire said, but now may need to be tailored for the African subtypes.

Some of the most effective weapons in the fight against HIV infection are protease inhibitors. These compounds are not AIDS vaccines, but can reduce the spread of the disease by binding to the HIV protease -- a key protein in the reproductive cycle of the virus.

In their study, the researchers introduced into the C and A proteases a common B-subtype mutation that could potentially be seen in African forms of the virus. The mutations, known to cause drug resistance in the B-subtype, enhance the biochemical "fitness" of the protease, making it better able to survive in the presence of HIV drugs.

The researchers found that the fitness of the C and A mutant proteases can be up to 1000-fold higher than that of the normal B subtype -- a significant increase over results from a previous study, where they reported that natural differences alone were responsible for increasing the biochemical fitness by a factor of 2-7.

"In other words," Freire explained, "the natural variations that exist in the protease of these African strains are not sufficient to cause resistance by themselves, but they amplify the effects of drug resistant mutations and, hence, may lead to a faster long-term failure of the therapy."

The research supports the argument that scientists need to broaden the focus of HIV drug development, which has been almost exclusively centered on HIV-B. However, Freire cautioned, "The experiments so far are at the biochemical level and a direct translation to a clinical response is not straightforward."

In the meantime, the findings do not justify withholding existing therapies from patients infected with African subtypes, Freire added. On the contrary: they emphasize the need to use existing therapies aggressively to suppress the emergence of mutations that cause drug resistance.

American Chemical Society

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