Taylor DL, Brennan T, Bridges CG, Mullins MJ, Jackson R, Cardin A; International Conference on AIDS.
Int Conf AIDS. 1993 Jun 6-11; 9: 480 (abstract no. PO-B26-2071).
MRC Collaborative Centre, Mill Hill, London.
The infection of T-lymphocytes and monocytes by HIV involves a specific high affinity interaction between the viral envelope glycoprotein gp120 and the CD4 cellular receptor, followed by fusion of the viral and cellular membranes. Heparin is known to exert its anti-HIV activity by antagonising this event, but its use as a therapeutic agent is limited by its potent anti-coagulant activity. A series of novel low molecular weight sulphonic acid polymers were synthesized as mimetics of heparin structure and function. In particular, MDL 101,028, composed of repeating monomers of biphenyl disulphonic acid structures joined by urea linkages, showed potent anti-HIV activity and negligible anti-coagulant effects. MDL 101,028 blocked the growth of a variety of HIV strains including clinical isolates and AZT resistant strains in established cell lines and human PBMCs determined by p24 antigen synthesis, syncytium formation and RT activity (IC50 range 0.5-3 micrograms/ml). In contrast to heparin, MDL 101,028 was a potent inhibitor of HIV-induced cell fusion when chronically infected H9 cells were co-cultured with uninfected CD4+ cells. This inhibition was seen even if the uninfected CD4+ cells only were pretreated with the polymer. Further studies in relation to the mechanism of action using a panel of monoclonal antibodies for different cell surface markers indicated a specific interaction with the CD4 antigen. Unlike heparin, MDL 101,028 did not inhibit the binding of radiolabelled HIV to CD4+ cells. This and other evidence points to potent antagonism of virus/host-cell fusion process. The novel mode of action, antiviral potency and lack of anti-coagulant activity suggest that MDL 101,028 may be of potential use for the treatment of HIV infections.
Publication Types:
Keywords:
- AIDS Vaccines
- Acquired Immunodeficiency Syndrome
- Antigens, CD4
- Antiviral Agents
- CD4-Positive T-Lymphocytes
- Cell Communication
- Cell Fusion
- Cell Line
- HIV
- HIV Antibodies
- HIV Envelope Protein gp120
- HIV Envelope Protein gp160
- HIV Infections
- HIV Seropositivity
- Humans
- Polymers
- Receptors, HIV
- Sulfonic Acids
- T-Lymphocytes
- Zidovudine
- immunology
Other ID:
UI: 102205057
From Meeting Abstracts