Divergent effects of cell environment on HIV entry inhibitor activity

作者：Rusert Peter; Mann Axel; Huber Michael; von Wyl Viktor; Guenthard Huldrych F; Trkola Alexandra^*

来源：AIDS, 2009, 23(11): 1319-1327.

DOI：10.1097/QAD.0b013e32832d92c2

• entry inhibitors
• HIV-1
• in-vitro inhibition assay
• neutralization
• pseudotyped virus

Objective: Successful HIV vaccine and entry inhibitor development depends on use of assay systems that closely reflect in-vivo activities. Recent reports suggest that the currently most widely used assay format, which relies on the genetically engineered target cell line TZM-bl, can fail to detect certain neutralization activities detected on primary peripheral blood mononuclear cell (PBMC)-based assay systems. In the present study, we investigate the influence the target cell context bears on HIV entry inhibition.
Design: In a comprehensive survey, the effect of 11 neutralizing antibodies and inhibitors in blocking entry of 30 envelope pseudotyped virus strains in two types of target cells, PBMC and TZM-bl, was evaluated.
Methods: Env-pseudotyped HIV infection of PBMC and TZM-bl cells.
Results: We demonstrate here that depending on the type of inhibitor, relative neutralization potencies are shifted to a variable extent and direction on TZM-bl and PBMC cells. In our assay set up, differences in inhibitor activity were solely effected by the target cell environment and amounted up to 2-3 logs lower activity on TZM-bl cells in several cases. Overall, neutralizing antibodies, 2612, 2F5 and 4E10, were less active in the TZM-bl system, whereas CD4 binding site directed inhibitor activities were detected equally well on both target cells, raising concerns that the TZM-bl assay may overrate the relevance of CD4 binding site specific responses.
Conclusion: Our data strongly argue that preclinical assessment should not be restricted to a single type of assay, as systematic underestimation or overestimation of activities would be inevitable.

• 出版日期2009-7-17
• 单位河北医科大学