Altered CD4 interactions of HIV type 1 LAI variants selected for the capacity to induce membrane fusion in the presence of a monoclonal antibody to domain 2 of CD4.
We selected HIV-1-LAI variants with the ability to induce syncytium formation of C8166 cells in the presence of a monoclonal antibody (MAb), 5A8, to domain 2 of CD4. Five biologically cloned variants with at least 60-fold greater resistance than wild type to 5A8-mediated inhibition of syncytium formation were obtained. The variants exhibited reduced relative sensitivity to inhibition of syncytium formation and virus infection, not only by the selecting anti-domain 2 MAb, but also by MAbs to domains 1 and 3 of CD4. By contrast, the sensitivity of these variants to neutralization by soluble CD4 and bivalent CD4-IgG was greater than for the parental clone. The affinities of soluble CD4 for Env protein, in either solubilized or membrane-anchored form, did not differ significantly between the variants and LAI. Analyses of sCD4-induced exposure of the transmembrane protein at 4 and 37 degrees C suggested, however, that the variants had acquired an increased susceptibility to the triggering of conformational changes in their Env oligomers at 37 degrees C. This may represent a mechanism of both the increased resistance to the CD4 MAbs and the enhanced sensitivity to soluble CD4.
Klasse
P J
PJ
Chester Beatty Laboratories, Institute of Cancer Research, London, UK.
Sattentau
Q J
QJ
D000911:Antibodies, Monoclonal / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D003001:Cloning, Molecular; D015726:Giant Cells / Q000821:virology*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008561:Membrane Fusion; D009363:Neoplasm Proteins / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D009363:Neoplasm Proteins; C042035:humoral leukocyte adherence inhibition factor, human