Sulfated polyanions prevent HIV infection of lymphocytes by disruption of the CD4-gp120 interaction, but do not inhibit monocyte infection.
Sulfated polyanions (SPs) bind variably to lymphocyte-expressed CD4 and inhibit binding of monoclonal antibodies to the first two domains of CD4. To further define this interaction, soluble recombinant CD4 (sCD4; four extracellular domains), its truncated amino-terminal two-domain derivative, and three linear peptide analogues spanning residues 6-60 (6-24, 20-40, 41-60) in the first domain were investigated for SP binding. Dextran sulfate (DXS) (500 kDa), polyvinyl sulfate, fucoidan, and carrageenan-kappa, each immobilized on carboxymethyl cellulose fibers, bound strongly to both the two-domain and four-domain recombinant CD4 molecules (similar to that observed with native CD4), whereas dextran sulfate (5 kDa), chondroitin 6-sulfate, and pentosan sulfate bound relatively poorly. No peptide binding to SPs was observed. Recombinant gp120 bound poorly (< 10%) to all of the immobilized polyanions, except pentosan sulfate (17%), for which some binding was noted. Binding of radiolabeled V3 loop peptide to SPs was slightly greater, with 20-30% binding to polyvinyl sulfate, dextran sulfate (500 kDa), and pentosan sulfate. Competitive binding studies demonstrated the predominance of sCD4 rather than rgp120 binding to SPs and supported previous data demonstrating a binding site for DXS (500 kDa) on the first domain of CD4 adjacent to the gp120 binding site and recognized by OKT4C and E monoclonal antibodies. Hence disruption of the CD4-gp120 interaction is probably responsible for most of the observed antiviral activity of SPs toward HIV infection of lymphocytes. However, HIV infection and gp120 binding to monocytes was unaffected by SPs, probably because SPs were unable to block the CD4-gp 120 interaction in monocytes.
Lynch
G
G
Department of Virology, Westmead Hospital, Australia.
Low
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L
Li
S
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Sloane
A
A
Adams
S
S
Parish
C
C
Kemp
B
B
Cunningham
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AL
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015704:CD4 Antigens / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D016264:Dextran Sulfate / Q000494:pharmacology; D004347:Drug Interactions; D006678:HIV / Q000302:isolation & purification; D015699:HIV Envelope Protein gp120 / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D015658:HIV Infections / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007457:Iodine Radioisotopes; D008214:Lymphocytes / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D010426:Pentosan Sulfuric Polyester / Q000494:pharmacology; D000071228:Polyelectrolytes; D011108:Polymers / Q000378:metabolism / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016264:Dextran Sulfate; D015699:HIV Envelope Protein gp120; D007457:Iodine Radioisotopes; D010426:Pentosan Sulfuric Polyester; D000071228:Polyelectrolytes; D011108:Polymers