LAMIVUDINE-RESISTANT HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 VARIANTS (184V) REQUIRE MULTIPLE AMINO-ACID CHANGES TO BECOME CO-RESISTANT TO ZIDOVUDINE IN-VIVO

Exposure of human immunodeficiency virus to the nucleoside analogue la mivudine (3TC) rapidly selects for resistant variants with a valine at codon 184 (M184V) in the catalytic site of reverse transcriptase. In vitro, 184V demonstrated increased enzyme fidelity and suppressed zido vudine resistance. Clinical trials demonstrated that 3TC-zidovudine co mbination therapy results in a strong and sustained antiviral response , To investigate the role of 184V on in vivo virus evolution, the effe ct of zidovudine addition in 3TC-pretreated patients harboring 184V wa s studied, In vivo, no significant change in fidelity was observed wit h 184V, shown by generation of the classical pattern of zidovudine mut ations, Of interest, in contrast to zidovudine monotherapy, in which j ust one substitution is sufficient for in vivo development of signific ant zidovudine resistance, multiple substitutions are required for the same level of zidovudine resistance in strains harboring 184V. This n eed for multiple substitutions may be one of the mechanisms explaining the sustained antiretroviral response of the 3TC-zidovudine combinati on.