COMPREHENSIVE MUTANT ENZYME AND VIRAL VARIANT ASSESSMENT OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE RESISTANCE TO NONNUCLEOSIDE INHIBITORS

The nonnucleoside reverse transcriptase (RT) inhibitors comprise a cla ss of structurally diverse compounds that are functionally related and specific for the human immunodeficiency virus type 1 RT. Viral varian ts resistant to these compounds arise readily in cell culture and in t reated, infected humans. Therefore, the eventual clinical usefulness o f the nonnucleoside inhibitors will rely on a thorough understanding o f the genetic and biochemical bases for resistance. A study was perfor med to assess the effects of substitutions at each RT amino acid resid ue that influences the enzyme's susceptibility to the various nonnucle oside compounds. Single substitutions were introduced into both purifi ed enzyme and virus. The resulting patterns of resistance were markedl y distinct for each of the tested inhibitors. For instance, a >50-fold loss of enzyme susceptibility to BI-RG-587 was engendered by any of f our individual substitutions, while the same level of relative resista nce to the pyridinone derivatives was mediated only by substitution at residue 181. Similarly, substitution at residue 106 had a noted effec t on virus resistance to BI-RG-587 but not to the pyridinones. The opp osite effect was mediated by a substitution at residue 179. Such knowl edge of nonnucleoside inhibitor resistance profiles may help in unders tanding the basis for resistant virus selection during clinical studie s of these compounds.