Anti-HIV-1 activity of chemically modified heparins: correlation between binding to the V3 loop of gp120 and inhibition of cellular HIV-1 infection in vitro.
Chemically modified heparins were tested for their activities in (i) inhibiting HIV-1 replication in vitro and (ii) inhibiting the binding to recombinant HIV-1 gp120 of monoclonal antibodies specific for the V3 loop. The results reveal that N-desulfation reduces activity, although this is largely restored on N-acetylation. Selective O-desulfation also markedly reduces activity, whereas carboxyl reduction has little effect. Overall these results show that the anti-HIV-1 activity of heparin does not depend simply on negative density, and indicate instead that particular structures, notably O-sulfates, are involved. Our studies reveal that for chemically modified heparins and heparin-derived fragments there is a striking correlation between anti-HIV-1 activity in vitro and binding to the V3 loop of gp120 in solid phase ELISA. This strongly suggests that the heparin exerts its anti-HIV-1 activity by binding to the V3 loop of gp120.
Rider
C C
CC
Department of Biochemistry, Royal Holloway and Bedford New College, Egham, Surrey, U.K.
Coombe
D R
DR
Harrop
H A
HA
Hounsell
E F
EF
Bauer
C
C
Feeney
J
J
Mulloy
B
B
Mahmood
N
N
Hay
A
A
Parish
C R
CR
D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000382:microbiology; D002417:Cattle; D004797:Enzyme-Linked Immunosorbent Assay; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects*; D006493:Heparin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013431:Sulfates; D013552:Swine
D000998:Antiviral Agents; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D013431:Sulfates; D006493:Heparin