Our new paper characterizes novel HIV-1 mutations selected by a RPV analog

Another part of Kevin's thesis was published in the Journal of Virology ("Two Coselected Distal Mutations in HIV-1 Reverse Transcriptase (RT) Alter Susceptibility to Nonnucleoside RT Inhibitors and Nucleoside Analogs"). This was an exciting collaboration with the Hughes Lab, in which they identified novel antiretroviral inhibitors that are analogs of the potent non-nucleoside inhibitor (NNRTI) rilpivirine that inhibit many rilpivirine-resistant HIV-1 mutants. After A LOT of persistence, Kevin was able to select resistant virus in the presence of the compounds. The most interesting mutant was selected by lucky rilpivirine analog #13, which had moderate resistance to all NNRTIs. Sequencing of the virus revealed two mutations (G112D and M230I) in reverse transcriptase (RT) that were quite far apart and had not been previously described.

Surprisingly, this mutant also had altered susceptibility to nucleoside analogs (NRTIs): hypersensitivity to AZT and resistance to FTC/3TC. Paul Boyer in the Hughes lab performed biochemical assays that determined that the two mutations, although far apart, interact with each other through the viral nucleic acid in the RT active site.