RESUMO
The entry of primate immunodeficiency viruses into target cells depends on a sequential interaction of the gp120 envelope glycoprotein with the cellular receptors, CD4 and members of the chemokine receptor family. The gp120 third variable (V3) loop has been implicated in chemokine receptor binding, but the use of the CCR5 chemokine receptor by diverse primate immunodeficiency viruses suggests the involvement of an additional, conserved gp120 element. Through the use of gp120 mutants, a highly conserved gp120 structure was shown to be critical for CCR5 binding. This structure is located adjacent to the V3 loop and contains neutralization epitopes induced by CD4 binding. This conserved element may be a useful target for pharmacologic or prophylactic intervention in human immunodeficiency virus (HIV) infections.
Assuntos
Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/química , Receptores CCR5/metabolismo , Substituição de Aminoácidos , Animais , Sítios de Ligação , Antígenos CD4/metabolismo , Cristalização , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/genética , Proteína gp120 do Envelope de HIV/imunologia , HIV-1/imunologia , Humanos , Modelos Moleculares , Fragmentos de Peptídeos/química , Conformação Proteica , Estrutura Secundária de Proteína , Proteínas Recombinantes/metabolismoRESUMO
Incorporation of the intercellular adhesion molecule ICAM-1 into human immunodeficiency virus type 1 (HIV-1) particles increased virus infectivity on peripheral blood mononuclear cells (PBMCs) by two- to sevenfold. The degree of ICAM-1-mediated enhancement was greater for viruses bearing envelope glycoproteins derived from primary HIV-1 isolates than for those bearing envelope glycoproteins from laboratory-adapted strains. Treatment of target PBMCs with an antibody against LFA-1, a principal ICAM-1 receptor, was able to nullify the ICAM-1-mediated enhancement. The incorporation of ICAM-1 rendered HIV-1 virions less susceptible to neutralization by a monoclonal antibody directed against the viral envelope glycoproteins. Surprisingly, an antibody against ICAM-1 completely neutralized infection by ICAM-1-containing viruses, reducing the efficiency of virus entry by almost 100-fold. Thus, HIV-1 neutralization by an ICAM-1-directed antibody involves more than an inhibition of the contribution of ICAM-1 to virus entry.
