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Journal of Virology, June 2005, p. 6703-6713, Vol. 79, No. 11
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.11.6703-6713.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Interaction with CD4 and Antibodies to CD4-Induced Epitopes of the Envelope gp120 from a Microglial Cell-Adapted Human Immunodeficiency Virus Type 1 Isolate

Julio Martín-García,^1* Simon Cocklin,^2, Irwin M. Chaiken,^2, and Francisco González-Scarano^1,3

Departments of Neurology,¹ Medicine,² Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania³

Received 16 November 2004/ Accepted 23 January 2005

We previously showed that the envelope glycoprotein from an in vitro microglia-adapted human immunodeficiency virus type 1 isolate (HIV-1_Bori-15) is able to use lower levels of CD4 for infection and demonstrates greater exposure of the CD4-induced epitope recognized by the 17b monoclonal antibody than the envelope of its parental, peripheral isolate (HIV-1_Bori). We investigated whether these phenotypic changes were related to a different interaction of their soluble monomeric gp120 proteins with CD4 or 17b. Equilibrium binding analyses showed no difference between Bori and Bori-15 gp120s. However, kinetic analysis of surface plasmon resonance-based, real-time binding experiments showed that while both proteins have similar association rates, Bori-15 gp120 has a statistically significant, 3-fold-lower dissociation rate from immobilized CD4 than Bori and a statistically significant, 14-fold-lower dissociation rate from 17b than Bori in the absence of soluble CD4. In addition, using the sensitivity to inhibition by anti-CD4 antibodies as a surrogate for CD4:trimeric envelope interaction, we found that Bori-15 envelope-pseudotyped viruses were significantly less sensitive than Bori pseudotypes, with four- to sixfold-higher 50% inhibitory concentration values for the three anti-CD4 antibodies tested. These differences, though small, suggest that adaptation to microglia correlates with the generation of a gp120 that forms a more stable interaction with CD4. Nonetheless, the observation of limited binding changes leaves open the possibility that HIV-1 adaptation to microglia and HIV-associated dementia may be related not only to diminished CD4 dependence but also to changes in other molecular factors involved in the infection process.

Present address: Department of Biochemistry, Drexel University College of Medicine, Philadelphia, PA 19102.

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