HIV infection is blocked in vitro by recombinant soluble CD4

Fisher, Richard A.; Bertonis, Jeanne M.; Meier, Werner; Johnson, Victoria A.; Costopoulos, Donna; Liu, Theresa; Tizard, Richard; Walker, Bruce D.; Hirsch, Martin S.; Schooley, Robert T.; Flavell, Richard A.

doi:10.1038/331076a0

Cited by 429 publications

(173 citation statements)

References 27 publications

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“…Aminoterminal sequence analysis demonstrated that our mature rCD4 molecule begins at the third residue of the published sequence; henceforth this residue (Asn) is referred to a position l . This is consistent with the findings of others [8,91 for their forms of recombinant CD4, and with the sequence observed for the homologous W3/25 antigen of rat [21].…”

Section: Carbohydrate Analysissupporting

confidence: 81%

Characterization of a soluble form of human CD4

Harris¹,

Chamow²,

Gregory³

et al. 1990

European Journal of Biochemistry

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CD4 is a glycoprotein that is expressed on the surface of a variety of cells of the immune system and is believed to participate in the interactions of these cells with antigen-presenting cells bearing the class I1 major histocompatability (MHC) antigens. CD4 also acts as the receptor for the human immunodeficiency virus (HIV) by binding to the viral glycoprotein gp120. Recombinant soluble CD4 (rCD4) is a truncated form of human CD4 that is secreted from transfected Chinese hamster ovary cells.This 368-amino-acid glycoprotein contains two potential sites of N-linked glycosylation (Asn-271 and Asn-300) and six cysteine residues. Amino-terminal sequence analysis demonstrated that the sequence begins at the third residue of the polypeptide originally predicted from the cDNA analysis [Maddon, P. J. et al. (1985) Cell 42, 93-1041. The rest of the primary sequence was confirmed by analysis of peptides purified by reversed-phase HPLC after digestion of S-carboxymethylated rCD4 with trypsin. Anhydrotrypsin affinity chromatography of trypsin-digested rCD4 confirmed that the carboxy-terminus of the protein was Pro-368. Enzymatic digestion of non-reduced rCD4 generated disulfide-bonded fragments that demonstrated the presence of disulfide bonds between Cys-16 and Cys-84, Cys-130 and Cys-159, and between Cys-303 and Cys-345.The constituent monosaccharides of the carbohydrate structures of rCD4 were found to be fucose, mannose, galactose, N-acetylglucosamine and N-acetylneuraminic acid. Characterization of the tryptic map of rCD4 after treatment with peptide: N-glycosidase F demonstrated that both potential N-glycosylation sites are utilized. The tryptic map of rCD4 treated with endo-/3-N-acetylglucosamine H demonstrated that only complex-type oligosaccharides are attached to Asn-271, while Asn-300 has high-mannose or hybrid structures attached in addition to complex-type oligosaccharides. Glucosamine was observed only in glycopeptides that contain Asn-300 or Asn-271 while no galactosamine was observed. This suggests that rCD4 contains no 0-linked oligosaccharides.

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Section: Carbohydrate Analysissupporting

confidence: 81%

Characterization of a soluble form of human CD4

Harris¹,

Chamow²,

Gregory³

et al. 1990

European Journal of Biochemistry

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“…Several studies suggest that CD4 may not only serve as a passive attachment site, but may also play an important role in the fusion process (Camerini & Seed, 1990;Celada et al, 1990;Healey et al, 1990). HIV infection is blocked in vitro by recombinant sCD4 (Deen et al, 1988;Fisher et al, 1988;Hussey et al, 1988). However, sCD4 poorly neutralizes fresh isolates of HIV-1 (Daar et al, 1990;Moore et aI., 1992).…”

Section: Discussionmentioning

confidence: 99%

Analysis of the human immunodeficiency virus type 1 envelope protein interaction with the CD4 host cell receptor

Malvoisin

Wild

1994

Journal of General Virology

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A secreted form of human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (gpl60s), expressed in HeLa cells from a vaccinia virus recombinant was analysed by velocity-gradient centrifugation and chemical cross-linking. We showed that gpl60s existed predominantly as a dimer, but higher forms corresponding to trimers and tetramers were also found. Soluble CD4 (sCD4) and native CD4 expressed by recombinant vaccinia viruses were analysed by sucrosegradient sedimentation alone or after complexing with gpl60s. The sCD4 sedimented in sucrose gradients as a monomer, whereas after solubilization the native CD4 was in a dimeric state. Both forms of CD4 were able to form complexes when incubated with gpl60s. In the case of the sCD4, the Mr corresponded to a (sCD4) 2-(gpl60s)2 complex, whereas with CD4 the complexes were of a greater order of magnitude. HIV gpl20 was secreted into the medium in a monomeric state, With sCD4 it gave a one-to-one complex, whereas with the native CD4 high M r complexes were formed. The importance of the oligomeric state of the virus-and cell-receptor proteins are discussed regarding their avidities.

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“…Despite the overall genetic heterogeneity of the gp120 glycoprotein, the conserved binding site, which interacts with CD4 receptor, provides an attractive antiviral target. The first attempt was to use soluble CD4 (sCD4) to block virus attachment [96]. Indeed, recombinant sCD4 had shown potent neutralizing activity against a variety of laboratory-adapted HIV strains, but exhibited low effectiveness against primary HIV isolates [97] and poor efficacy in vivo.…”

Section: Hiv-1 Gp120 Inhibitorsmentioning

confidence: 99%