Divergent effects of cell environment on HIV entry inhibitor activity

Rusert, Petera; Mann, Axela; Huber, Michaelb; von Wyl, Viktorb; Günthard, Huldrych Fb; Trkola, Alexandraa

doi: 10.1097/QAD.0b013e32832d92c2
Basic Science

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, 2G12, 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.

Author Information

aInstitute of Medical Virology, University of Zurich, Switzerland

bDivision of Infectious Diseases, University Hospital Zurich, Zurich, Switzerland.

Received 4 December, 2008

Revised 24 March, 2009

Accepted 30 April, 2009

Correspondence to Alexandra Trkola, Institute of Medical Virology, University of Zurich, Gloriastrasse 30, 8006 Zurich, Switzerland. Tel: +41 44 634 53 80; fax: +41 44 634 49 67; e-mail: trkola.alexandra@virology.uzh.ch

© 2009 Lippincott Williams & Wilkins, Inc.