HIV-1 develops resistance to one common antiretroviral drug, AZT, through mutations that increase the rate of excision of the drug from viral DNA. This report, published online this week in Nature Structural & Molecular Biology, provides a basis for the development of drugs that could inhibit drug excision and possibly lead to more effective forms of treatment in the future.
AZT was the first approved drug to treat patients with HIV-1, and it is still a component of the antiretroviral therapy. Like a large number of antiretroviral drugs, AZT targets the viral enzyme reverse transcriptase (RT) — which is essential in producing viral DNA for the multiplication of the virus.
To understand why some HIV-1 RT mutants can remove AZT from the viral DNA, Eddy Arnold and colleagues characterized the crystal structures of mutant HIV-1 RT with different forms of AZT. They found that the mutations create a novel binding site on the protein for ATP, which participates in the AZT removal reaction from the viral DNA.