Gao Q, Parniak M A, Gu Z, Wainberg M A
Lady Davis Institute, Jewish General Hospital, Còte Ste-Catherine, Montreal, Quebec, Canada.
Leukemia. 1992;6 Suppl 3:192S-195S.
Several laboratories have shown that AZT-resistant variants of HIV-1 can be isolated from patients who have received prolonged therapy with this drug. Our laboratory has now been able to generate HIV-1 variants resistant to both AZT and ddI, in tissue culture, by using step-wise increases in the concentrations of each of these compounds over a 10-week period. This work has been performed by culturing wild-type clinical strains of HIV-1 as well as the HIV-3b laboratory strain of this virus under such conditions. The ID50 values obtained for the resistant viruses thus generated vary between 50-100 times above those of the parental wild-type strains in each case. Furthermore, we have identified several new mutation sites in the HIV-1 pol gene that are responsible for the observed resistance to AZT and ddI. We have not succeeded, however, in generating drug-resistant strains of HIV-1, under conditions in which several compounds or anti-viral agents were simultaneously present during the in vitro selection process. Combinations of drugs which failed to yield drug-resistant variants included AZT plus ddI, AZT plus alpha-interferon, and ddI plus alpha-interferon. These findings indicate that HIV drug resistance is less likely to occur in tissue culture when combinations of drugs are used, and provide rationale for the development of combination clinical trials for treatment of HIV-associated disease.
几个实验室已表明，从接受过这种药物长期治疗的患者中可以分离出对齐多夫定（AZT）耐药的HIV-1变异株。我们实验室现在已经能够通过在10周时间内逐步提高这两种化合物的浓度，在组织培养中产生对AZT和双脱氧肌苷（ddI）都耐药的HIV-1变异株。这项工作是在这样的条件下，通过培养HIV-1的野生型临床毒株以及该病毒的HIV-3b实验室毒株来完成的。如此产生的耐药病毒的半数感染剂量（ID50）值在每种情况下都比亲代野生型毒株高出50至100倍。此外，我们已经在HIV-1逆转录酶基因中确定了几个新的突变位点，这些位点导致了观察到的对AZT和ddI的耐药性。然而，在体外选择过程中同时存在几种化合物或抗病毒药物的条件下，我们未能成功产生HIV-1耐药毒株。未能产生耐药变异株的药物组合包括AZT加ddI、AZT加α干扰素以及ddI加α干扰素。这些发现表明，使用药物组合时在组织培养中产生HIV耐药性的可能性较小，并为开展治疗HIV相关疾病的联合临床试验提供了理论依据。
