Critical role of Arg⁵⁹ in the high-affinity gp120-binding region of CD4 for human immunodeficiency virus type 1 infection

Human immunodeficiency virus type 1 (HIV-1) infection is initiated by the binding of the viral envelope protein gp120 to the host cell CD4 receptor through a high-affinity interaction involving amino acids 39-60 within the CD4. We obtained evidence demonstrating functional importance of this region in CD4 for viral infectivity by showing that a synthetic peptide corresponding to this CD4 sequence exhibited competitive binding to gp120 and significantly reduced infection by diverse HIV-1 strains, including primary isolates. Treatment of HIV-1-infected cells with this CD4 peptide induced shedding of gp120 and exposure of the transmembrane protein gp41. Furthermore, we observed that deletion or substitution of arginine at position 59 (Arg⁵⁹) within the CD4 peptide sequence abrogated its gp120-shedding property. These results indicate a critical role for Arg⁵⁹ in the CD4 for conformational changes in gp120 during the sequential process of entry and infection by HIV-1.