AEGiS-13IAC: Comparative and combinatorial analysis of the HIV-1 entry inhibitors PRO 542, T-20 and PRO 140.

13th International AIDS Conference

Durban, South Africa - July 9-July 14, 2000

Comparative and combinatorial analysis of the HIV-1 entry inhibitors PRO 542, T-20 and PRO 140.

Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. WeOrA533)

Olson W, Nagashima K, Rosenfield S, Maddon P
W. Olson, Progenics Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, United States, Tel.: +1 914 789 2800, Fax: +1 914 789 2807, E-mail: olson@progenics.com

BACKGROUND: There is an urgent need for new therapies that target novel stages of the HIV-1 replicative cycle, such as viral entry. PRO 542 (CD4-IgG2) is a fusion protein in which the heavy and light chain constant regions of human IgG2 have been replaced with four copies of the D1D2 domains of human CD4. PRO 542 has demonstrated broad-based antiviral activity in numerous preclinical models of HIV-1 infection as well in Phase I/II clinical trials in HIV infected adults and children. T-20 is a peptide derived from the HIV-1 envelope glycoprotein gp41. In Phase I/II studies, T-20 significantly reduced blood levels of HIV in infected individuals. PRO 140 is a monoclonal antibody to CCR5 that potently blocks HIV-1 entry but not CC-chemokine signaling through CCR5. Each of these agents thus inhibits viral entry by a distinct mechanism. In this study, we explored the antiviral properties of these promising new agents when used alone and in combination.

METHODS: The antiviral activities of these agents and their combinations were examined using a rapid and automated assay that measures HIV-1 env-mediated membrane fusion. The inhibition data were used to determine the inhibitory doses of the agents and combinations as well as their synergistic, additive or antagonistic effects.

RESULTS: Potent synergies were observed for certain combinations of HIV-1 entry inhibitors. In such instances, the drug levels required to achieve clinically relevant levels of inhibition were reduced 5- to 15-fold. Additive effects were observed with other combinations. No agent antagonized the activity of another.

CONCLUSIONS: HIV-1 entry can be potently inhibited by combinations of agents that act at distinct but potentially interdependent stages of the viral entry process. These findings provide strong rationale for evaluating combinations of such agents for the treatment of HIV-1 infected individuals.

Keywords: AEGIS, CD4 Immunoadhesins, HIV Envelope Protein gp41, Anti-HIV Agents, HIV-1, Peptide Fragments, HIV Infections, Antigens, CD4, Membrane Fusion, Chemokines, CC, CD4-IgG(2), pentafuside, PRO 140, Adult, Child, Human, antagonists & inhibitors, immunology
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