Nijhuis M, Schuurman R, de Jong D, van Leeuwen R, Lange J, Danner S, Keulen W, de Groot T, Boucher C A
Eijkman-Winkler Institute, Department of Virology, University Hospital Utrecht, Netherlands.
J Infect Dis. 1997 Aug;176(2):398-405. doi: 10.1086/514056.
Exposure of human immunodeficiency virus to the nucleoside analogue lamivudine (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 zidovudine resistance. Clinical trials demonstrated that 3TC-zidovudine combination therapy results in a strong and sustained antiviral response. To investigate the role of 184V on in vivo virus evolution, the effect of zidovudine addition in 3TC-pretreated patients harboring 184V was studied. In vivo, no significant change in fidelity was observed with 184V, shown by generation of the classical pattern of zidovudine mutations. Of interest, in contrast to zidovudine monotherapy, in which just one substitution is sufficient for in vivo development of significant zidovudine resistance, multiple substitutions are required for the same level of zidovudine resistance in strains harboring 184V. This need for multiple substitutions may be one of the mechanisms explaining the sustained antiretroviral response of the 3TC-zidovudine combination.
人类免疫缺陷病毒暴露于核苷类似物拉米夫定（3TC）后，会迅速筛选出逆转录酶催化位点密码子184处为缬氨酸（M184V）的耐药变异株。在体外，184V表现出更高的酶保真度并抑制了齐多夫定耐药性。临床试验表明，3TC-齐多夫定联合疗法可产生强大且持续的抗病毒反应。为了研究184V在体内病毒进化中的作用，对在携带184V的3TC预处理患者中添加齐多夫定的效果进行了研究。在体内，通过产生齐多夫定突变的经典模式表明，184V未观察到保真度的显著变化。有趣的是，与齐多夫定单药治疗不同，在齐多夫定单药治疗中，仅一个替换就足以在体内产生显著的齐多夫定耐药性，而在携带184V的毒株中，产生相同水平的齐多夫定耐药性则需要多个替换。这种对多个替换的需求可能是解释3TC-齐多夫定联合疗法持续抗逆转录病毒反应的机制之一。
