title: Interaction with CD4 and antibodies to CD4-induced epitopes of the envelope gp120 from a microglial cell-adapted human immunodeficiency virus type 1 isolate.
abstract: 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.
authors.affiliation: Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6146, USA. jumartin@mail.med.upenn.edu
authors.forename: Julio
authors.initials: J
authors.lastname: Martín-García
authors.forename: Simon
authors.initials: S
authors.lastname: Cocklin
authors.forename: Irwin M
authors.initials: IM
authors.lastname: Chaiken
authors.forename: Francisco
authors.initials: F
authors.lastname: González-Scarano
mesh_terms: D015526:AIDS Dementia Complex / Q000209:etiology / Q000276:immunology / Q000821:virology; D000222:Adaptation, Physiological; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001483:Base Sequence; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens / Q000378:metabolism*; D002460:Cell Line; D004279:DNA, Viral / Q000235:genetics; D000939:Epitopes / Q000235:genetics / Q000378:metabolism; D015483:HIV Antibodies / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D017628:Microglia / Q000821:virology*
chemical_list: D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; D004279:DNA, Viral; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120