Genotypic, phenotypic, and modeling studies of a deletion in the beta 3-beta 4 region of the human immunodeficiency virus type 1 reverse transcriptase gene that is associated with resistance to nucleoside reverse transcriptase inhibitors

Point mutations and inserts in the beta3-beta4 region of human immunodefici ency virus type I OW-l) reverse transcriptase (RT) are associated with resi stance to nucleoside analog inhibitors. This report describes HIV-I strains from seven patients that were found to have a 3-bp deletion in the beta3-b eta4 region of the RT gene. These patient strains also had a mean of 6.2 dr ug resistance-associated mutations in their RT genes (range, 3 to 10 mutati ons). The deletion was most frequently found in strains with the Q151M muta tion. Nonnucleoside RT inhibitor mutations were found in six of seven strai ns. Culture-based drug sensitivity assays showed that deletion-containing i solates had reduced susceptibility to four to eight RT inhibitors. Site-dir ected mutagenesis experiments showed that the deletion alone conferred redu ced susceptibility to nucleoside analogs. Changes in the three-dimensional models of the RT deletion mutants were consistently observed at the beta3-b eta4 loop and at helices C and E in both the presence and the absence of dT TP. Loss of hydrogen bonds between the RT and dTTP were also observed in th e RT deletion mutant. These results suggest that the deletion in the RT gen e contributes to resistance to several nucleoside analogs through a complex interaction with other mutations in the RT gene.