A mutation in a little-studied structural region of the AIDS virus can cause resistance to several HIV drugs, according to a study published in PLoS Medicine by Gilda Tachedjian and colleagues from Australia, Canada, and the United States.
Several mutations in reverse transcriptase (RT), the viral enzyme that copies the genes of HIV, are already known to cause drug resistance and are routinely detected in blood tests used by physicians to individualize HIV treatment. The mutation in this study, designated N348I, is located not in the active part of RT, but rather in the so-called connection domain, which falls outside the region of the virus normally included in resistance tests.
The researchers analyzed the first two-thirds of the RT gene in viruses isolated from more than 1,000 patients in Canada, and found that virus carrying the N348I mutation developed in more than 10% of treatment-experienced patients. Patients treated with the HIV drugs zidovudine and nevirapine were 2.6-times more likely to have the N348I mutation than patients not treated with these drugs.
The mutation appeared early in therapy, often in viruses that had other resistance mutations. Furthermore, the appearance of the N348I mutation often coincided with an increase in the amount of HIV present in blood. When the researchers introduced the N348I mutation into HIV growing in the laboratory, they found that it decreased the susceptibility of the virus to drugs.
Because the N348I mutation confers resistance to two classes of RT inhibitor drugs and can emerge early during therapy, it could have a large impact on patient responses to antiviral regimens that contain zidovudine and nevirapine. It might now be worth investigating whether looking for the N348I mutation (and for other mutations outside the region of RT included in current tests) could improve the ability of resistance tests to predict treatment outcomes.
Citation: Yap SH, Sheen CW, Fahey J, Zanin M, Tyssen D, et al. (2007) N348I in the connection domain of HIV-1 reverse transcriptase confers zidovudine and nevirapine resistance. PLoS Med 4(12): e335
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