• Understanding HIV-1 Drug Resistance: From Basic Science to Clinical Practice (Abstract PL12)
  Speaker: J. Mellors
  Authored by Mellors, J.; Division of Inf. Diseases, University of Pittsburgh, PA, USA

John Mellors was in charge of reviewing resistance testing. He quickly focused on nucleoside resistance. He gave a superb talk (as usual), although it was highly technical with lots of 3D imaging of reverse transcriptase and different nucleotides that I think was difficult to follow for most of the audience (it was definitely tough for me).

I did not know that most nucleoside analogs have L and D forms (what this means is that some molecules can have two forms: left and right that are mirror images of themselves). In some nucleotides only the L forms are active. These L nucleosides tend to select mutations in position M184 of the reverse transcriptase molecule and substitute that residue with a V or and I (different amino acids). You guessed right if you thought that 3TC belongs to this category. In general, we have one shot when we use this L-nucleosides, because cross-resistance is common. D-nucleosides are a different story. They select mutations in the "finger" of the reverse transcriptase like 65R and 70N/E. We might have a chance for sequencing of these nucleosides.

Then he summarized some of the mechanisms that mediate AZT resistance. This involves the excision of AZT mono phosphate from the elongating chain of DNA. When AZT mono phosphate is added to the elongating chain of DNA it can be removed by pyrophosphorolysis and in this case the process of replicating the RNA into DNA can continue or the next nucleotide can be added to the chain. If that happens it is a dead end for the replicating DNA because this nucleotide is not "bound" to the previous one. (This is easy if you see it in a slide. This mechanism has been elucidated the last couple of years, and represents a potential target for new drugs for the treatment of HIV.)

Dr. Mellors talks have become increasingly complex for us mortals, but his work in resistance is very important and helps in the development of new drugs and molecules that are not cross-resistant to the currently available therapies.

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