Malkevitch N, McDermott D H, Yi Y, Grivel J C, Schols D, De Clercq E, Murphy P M, Glushakova S, Collman R G, Margolis L
Laboratory of Molecular and Cellular Biophysics, National Institutes of Health, Bethesda, Maryland 20892, USA.
Virology. 2001 Mar 15;281(2):239-47. doi: 10.1006/viro.2000.0807.
Coreceptor utilization by HIV-1 is an important determinant of pathogenesis. However, coreceptor selectivity is defined in vitro, while in vivo critical pathogenic events occur in lymphoid tissues. Using pharmacological inhibitors, we recently provided evidence that coreceptor selectivity by the R5X4 dual-tropic isolate 89.6 was more restricted in ex vivo infected lymphoid tissue than in vitro [S. Glushakova, Y. Yi, J. C. Grivel, A. Singh, D. Schols, E. De Clercq, R. G. Collman, and L. Margolis (1999). J. Clin. Invest. 104, R7-R11]. Here we extend those observations using CCR5-deficient (CCR5Delta32) lymphoid tissue as well as additional primary isolates. We definitively show that neither CCR5 nor secondary coreceptors used in vitro mediate 89.6 infection in lymphoid tissue. We also demonstrate that restricted coreceptor use in lymphoid tissue ex vivo compared with in vitro utilization occurs with other dual-tropic primary isolates and is not unique to 89.6. For all strains tested that are dual tropic in vitro, severe CD4 T cell depletion in lymphoid tissue correlated with preferential CXCR4 use in this ex vivo system.
HIV-1对共受体的利用是发病机制的一个重要决定因素。然而，共受体选择性是在体外定义的，而体内关键的致病事件发生在淋巴组织中。我们最近使用药理学抑制剂提供了证据，表明R5X4双嗜性分离株89.6对共受体的选择性在体外感染的淋巴组织中比在体外更受限制[S. Glushakova, Y. Yi, J. C. Grivel, A. Singh, D. Schols, E. De Clercq, R. G. Collman, and L. Margolis (1999). J. Clin. Invest. 104, R7-R11]。在这里，我们使用CCR5缺陷（CCR5Delta32）淋巴组织以及其他原代分离株扩展了这些观察结果。我们明确表明，体外使用的CCR5和二级共受体都不能介导89.6在淋巴组织中的感染。我们还证明，与体外利用相比，其他双嗜性原代分离株在体外淋巴组织中对共受体的利用也受到限制，这并非89.6所特有。对于所有在体外具有双嗜性的测试菌株，淋巴组织中严重的CD4 T细胞耗竭与该体外系统中对CXCR4的优先利用相关。
