DORR PK, CORBAU R, PICKFORD C, RICKETT G, MACARTNEY M, GRIFFIN P, DOBBS S, IRVINE R, WESTBY M, PERROS M; Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2003 Sep 14-17; 43: abstract no. F-1466.

Pfizer Global R&D, Sandwich, United Kingdom.

BACKGROUND: Recently described CCR5 antagonists are thought to inhibit HIV-1 entry into the host cell by occupying a specific site on the receptor, thus preventing attachment of the envelope protein gp120. While this simple model may be true in some cases, it is also possible that inhibitors affect the receptor in such a way that it is less effective in binding the viral envelope, or enabling the subsequent steps leading to membrane fusion. METHODS: We evaluated the potency of ~50 small-molecule inhibitors against chemokine and gp120 binding, as well as against gp160-induced cell-cell fusion. We used FACS to evaluate the ability of selected compounds to induce CCR5 internalization, and looked for intracellular signaling by Ca[2+]-flux experiments or gS-GTP labeling. RESULTS: The ability of the inhibitors to prevent viral replication was strongly correlated with their activity against cell fusion (r[2]>0.7), but only weakly with their potency against either chemokine or gp120 binding. The compounds did not trigger CCR5 internalization or induce intracellular signaling. The observed differences in translation from binding activity to fusion or antiviral activity were reproducible from assay to assay. CONCLUSIONS: The ability of experimental CCR5 antagonists to inhibit HIV-1 induced membrane fusion and viral replication, is only partly explained by their affinity for the receptor and ability to prevent gp120 binding. The weak correlation between binding inhibition and anti-fusion activity indicates that the inhibitors can also affect viral entry at a step subsequent to viral attachment, raising the interesting possibility that the role of CCR5 in viral entry is not limited to binding gp120.

Publication Types:

• Meeting Abstracts

Keywords:

• AIDS Vaccines
• Acquired Immunodeficiency Syndrome
• Cell Fusion
• Chemokines
• Gene Products, env
• HIV Envelope Protein gp120
• HIV Infections
• HIV Seropositivity
• HIV-1
• Membrane Fusion
• Receptors, CCR5
• Signal Transduction
• immunology
• methods

Other ID:

• GWAIDS0026772

UI: 102266396

From Meeting Abstracts