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| |  Removal Of Chain Terminators By HIV-1 Reverse Transcriptase: Presented at HIV-DART By Marc S. Berger, MD Special to DG News SAN JUAN, PUERTO RICO -- December 29, 2000 -- HIV can develop resistance to zidovudine (AZT, Retrovir) when reverse transcriptase develops mutations that accelerate its repair of terminated DNA chains. Reverse transcriptase (RT) uses cellular adenosine triphosphate (ATP) to remove the false nucleoside blocking strand elongation, according to Walter Scott and Peter Meyer, researchers at the University of Miami, Miami, Florida, who spoke recently at the Frontiers in Drug Development for Antiretroviral Therapies (DART) meeting, in San Juan, Puerto Rico. Normally, reverse transcriptase creates cDNA strands from viral RNA templates, incorporating triphosphorylated nucleotides into the cDNA. When the false nucleotide AZT triphosphate is incorporated instead of ATP, viral replication stops. However, reverse transcriptase can also catalyze another, separate reaction, where the last nucleotide is cleaved off the chain, using energy from ATP or pyrophosphate. If this nucleotide is AZT, the chain is then no longer terminated, and cDNA synthesis can resume, along with viral replication. This is one mechanism for the resistance of HIV mutants to AZT. Drs. Scott and Meyer have shown that AZT-resistant mutants still incorporate AZT triphosphate into the DNA strand, but have increased catalytic efficiency for the ATP-dependent terminal nucleotide cleavage, compared with the wild type RT. Different biochemical mutations have different rates of AZT excision/repair. They have also shown that the three-dimensional structure of viral RT reveals a different enzymatic site for the excision of the terminal nucleoside, and that amino acid substations in RT may change the affinity of this site without affecting the RT site. This mechanism, however, may not be a major factor in the resistance noted with other nucleoside RT inhibitors. While this model explains some clinical observations, and may lead to better understanding of the resistance mechanism of other nucleoside RT inhibitors, it clearly does not explain all observed AZT resistance. For example, it does not explain why there is clinically noted cross-resistance between AZT and d4T (stavudine)-resistant strains. The antiviral drug, foscarinet, has been shown to work partially by inhibiting this terminal nucleoside excision and may restore sensitivity to mutants that are AZT-resistant by this mechanism.
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