Been-Tiktak A M, de Haas C J, de Graaf L, Boucher C A, Verhoef J, Borleffs J C, Nottet H S, Schuurman R
Eijkman-Winkler Institute of Medical Microbiology, University of Utrecht, University Hospital, The Netherlands.
J Antimicrob Chemother. 1997 Dec;40(6):847-53. doi: 10.1093/jac/40.6.847.
Unlike the selection of HIV-1 variants resistant to anti-retroviral drugs in human peripheral blood mononuclear cells and T cell lines, induction of resistance in monocyte-derived macrophages has not been widely studied. Since macrophages serve as a potential HIV-1 reservoir in humans, knowledge of the effect of anti-retroviral drugs on macrophage-tropic HIV-1 isolates may help in the design of a strategy for prolonged suppression of viral replication. In-vitro selection and drug susceptibility testing of macrophage-tropic HIV-1 variants with reduced sensitivity to two non-nucleoside reverse transcriptase inhibitors, atevirdine and delavirdine (both bis-heteroarylpiperazines), is described here. The atevirdine-resistant isolate was cross-resistant to delavirdine, and the delavirdine-resistant isolate was cross-resistant to atevirdine. Interestingly, the atevirdine-resistant isolate, but not the delavirdine-resistant isolate, was also cross-resistant to nevirapin while the inhibition of viral replication of both isolates in macrophages by zidovudine was the same as that in the parental HIV-1 strain. Nucleotide sequence analysis of the resistant macrophage-tropic HIV-1 isolates showed that the atevirdine-induced resistance was due to a single amino acid change at codon 106 and that the delavirdine-induced resistance could be attributed to an amino acid change at codon 236. This study demonstrates that monocyte-derived macrophages can be used to investigate the phenotypic and genotypic acquisition of anti-retroviral drug resistance of macrophage-tropic HIV-1.
与在人类外周血单核细胞和T细胞系中选择对抗逆转录病毒药物耐药的HIV-1变体不同，单核细胞衍生的巨噬细胞中耐药性的诱导尚未得到广泛研究。由于巨噬细胞是人类潜在的HIV-1储存库，了解抗逆转录病毒药物对嗜巨噬细胞HIV-1分离株的影响可能有助于设计长期抑制病毒复制的策略。本文描述了对两种非核苷类逆转录酶抑制剂阿替韦啶和地拉韦啶（均为双杂芳基哌嗪）敏感性降低的嗜巨噬细胞HIV-1变体的体外选择和药物敏感性测试。阿替韦啶耐药株对地拉韦啶交叉耐药，地拉韦啶耐药株对阿替韦啶交叉耐药。有趣的是，阿替韦啶耐药株对奈韦拉平也交叉耐药，而地拉韦啶耐药株则不然，同时齐多夫定对两种分离株在巨噬细胞中病毒复制的抑制作用与对亲本HIV-1株的抑制作用相同。对耐药嗜巨噬细胞HIV-1分离株的核苷酸序列分析表明，阿替韦啶诱导的耐药性是由于密码子106处的单个氨基酸变化，而地拉韦啶诱导的耐药性可归因于密码子236处的氨基酸变化。这项研究表明，单核细胞衍生的巨噬细胞可用于研究嗜巨噬细胞HIV-1抗逆转录病毒药物耐药性的表型和基因型获得情况。
