Progenics Pharmaceuticals, Inc.

Virginia M Litwin

Paul J Maddon

Graham P Allaway

William C Olson

This invention provides methods for inhibiting fusion of HIV-1 to CD4cells which comprise contacting CD4cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4cells is inhibited. This invention also provides methods for inhibiting HIV-1 infection of CD4cells which comprise contacting CD4cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4cells is inhibited, thereby inhibiting the HIV-1 infection. This invention provides non-chemokine agents capable of binding to the chemokine receptor and inhibiting fusion of HIV-1 to CD4cells. This invention also provides pharmaceutical compositions comprising an amount of the non-chemokine agent capable of binding to the chemokine receptor and inhibiting fusion of HIV-1 to CD4cells effective to prevent fusion of HIV-1 to CD4cells and a pharmaceutically acceptable carrier.

CCR5 chemokine receptor-specific monoclonal antibodies capable of inhibiting HIV-1 cell fusion

This invention provides: agents determined to be capable of specifically inhibiting the fusion of a macrophage-tropic primary isolate of HIV-1 to a CD4cell, but not a T cell-tropic isolate of HIV-1 to a CD4cell; and agents determined to be capable of specifically inhibiting the fusion of a T cell-tropic isolate of HIV-1 to a CD4cell, but not a macrophage-tropic primary isolate of HIV-1 to a CD4+ cell. This invention also provides: agents capable of specifically inhibiting the fusion of a macrophage tropic primary isolate of HIV-1 with a CD+ cell susceptible to infection by a macrophage-tropic primary isolate of HIV-1; and agents capable of specifically inhibiting the fusion of a T cell-tropic isolate of HIV-1 with a CD4cell susceptible to infection by a T cell-tropic isolate of HIV-1. The agents include but are not limited to antibodies. This invention further provides: methods of inhibiting fusion of a macrophage-tropic primary isolate of HIV-1 with a CD+ cell susceptible to infection by a macrophage-tropic primary isolate of HIV-1 which comprises contacting the CD4cell with an amount of an agent capable of specifically inhibiting such fusion so as to thereby inhibit such fusion; and methods of inhibiting fusion of a T cell-tropic isolate of HIV-1 with a CD4cell susceptible to infection by a T cell-tropic isolate of HIV-1 which comprises contacting the CD4cell with an amount of an agent capable of specifically inhibiting such fusion so as to thereby inhibit such fusion.

Methods for assaying inhibition of HIV-1 envelope glycoprotein-mediated membrane fusion

This invention provides agents determined to be capable of inhibiting the fusion of a macrophage-tropic primary isolate of HIV-1 to a CD4cell and agents determined to be capable of inhibiting the fusion of a T cell-tropic isolate of HIV-1 to a CD4cell. This invention also provides methods to identify such agents. This invention further provides methods of inhibiting fusion of a macrophage-tropic primary isolate of HIV-1 with a CD+ cell and methods of inhibiting fusion of a T cell-tropic isolate of HIV-1 with a CD4cell susceptible to infection by a T cell-tropic isolate of HIV-1.

Methods for inhibiting HIV-1 envelope glycoprotein-medicated membrane fusion

Methods of inhibiting human immunodeficiency virus type 1 (HIV-1) infection through the administration of CCR5 chemokine receptor antagonists

This invention provides an antibody capable of specifically inhibiting the fusion of an HIV-1 envelope glycoproteincell with an appropriate CD4cell without cross reacting with the HIV-1 envelope glycoprotein or CD4 and capable of inhibiting infection by one or more strains of HIV-1. This antibody is then used to identify a molecule which is important for HIV infection. Different uses of the antibody and the molecule are described.

Compounds capable of inhibiting HIV-1 infection

Methods for inhibiting HIV-1 infection

This invention provides: agents determined to be capable of specifically inhibiting the fusion of a macrophage-tropic primary isolate of HIV-1 to a CD4cell, but not a T cell-tropic isolate of HIV-1 to a CD4cell; and agents determined to be capable of specifically inhibiting the fusion of a T cell-tropic isolate of HIV-1 to a CD4cell, but not a macrophage-tropic primary isolate of HIV-1 to a CD4cell. This invention also provides: agents capable of specifically inhibiting the fusion of a macrophage tropic primary isolate of HIV-1 with a CD+ cell susceptible to infection by a macrophage-tropic primary isolate of HIV-1; and agents capable of specifically inhibiting the fusion of a T cell-tropic isolate of HIV-1 with a CD4cell susceptible to infection by a T cell-tropic isolate of HIV-1. The agents include but are not limited to antibodies. This invention further provides: methods of inhibiting fusion of a macrophage-tropic primary isolate of HIV-1 with a CD+ cell susceptible to infection by a macrophage-tropic primary isolate of HIV-1 which comprises contacting the CD4cell with an amount of an agent capable of specifically inhibiting such fusion so as to thereby inhibit such fusion; and methods of inhibiting fusion of a T cell-tropic isolate of HIV-1 with a CD4cell susceptible to infection by a T cell-tropic isolate of HIV-1 which comprises contacting the CD4cell with an amount of an agent capable of specifically inhibiting such fusion so as to thereby inhibit such fusion.

Methods for using resonance energy transfer-based assay of HIV-1 envelope glycoprotein-mediated membrane fusion, and kits for practicing same

This invention provides methods for inhibiting fusion of HIV-1 to CD4 cells which comprise contacting CD cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4 cells is inhibited. This invention also provides methods for inhibiting HIV-1 infection of CD4 cells which comprise contacting CD4 cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4 cells is inhibited, thereby inhibiting the HIV-1 infection. This invention provides non-chemokine agents capable of binding to the chemokine receptor and inhibiting fusion of HIV-1 to CD4 cells. This invention also provides pharmaceutical compositions comprising an amount of the non-chemokine agent capable of binding to the chemokine receptor and inhibiting fusion of HIV-1 to CD4 cells effective to prevent fusion of HIV-1 to CD4 cells and a pharmaceutically acceptable carrier.

Method for preventing HIV-1 infection of CD4&plus; cells

Previous studies of human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein-mediated membrane fusion have focused on laboratory-adapted T-lymphotropic strains of the virus. The goal of this application was to develop a novel screening assay to characterize membrane fusion mediated by a primary HIV-1 isolate in comparison with a laboratory-adapted strain. To this end, a novel fusion assay was developed on the basis of the principle of resonance energy transfer, using HeLa cells stably transfected with gp120/gp41 from the T-lymphotropic isolate HIV-1,or the macrophage-tropic primary isolate HIV-1,. These cells fused with CD4,target cell lines with a tropism mirroring that of infection by the two viruses. Of particular note, HeLa cells expressing HIV-1,gp120/gp41 fused only with PM1 cells, a clonal derivative of HUT 78, and not with other T-cell or macrophage cell lines. These results demonstrate that the envelope glycoproteins of these strains play a major role in mediating viral tropism. Despite significant differences exhibited by HIV-1,and HIV-1,in terms of tropism and sensitivity to neutralization by CD4-based proteins, the present study found that membrane fusion mediated by the envelope glycoproteins of these viruses had remarkably similar properties. In particular, the degree and kinetics of membrane fusion were similar, fusion occurred at neutral pH and was dependent on the presence of divalent cations. The claimed invention will facilitate the screening and identification of novel agents that are capable of inhibiting these interactions.

Fluorescence resonance energy transfer screening assay for the identification of compounds that are capable of abrogating macrophage-tropic HIV-1 cell fusion

This invention provides methods for inhibiting fusion of HIV-1 to CD4.sup.+ cells which comprise contacting CD4.sup.+ cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4.sup.+ cells is inhibited. This invention also provides methods for inhibiting HIV-1 infection of CD4.sup.+ cells which comprise contacting CD4.sup.+ cells with a non-chemokine agent capable of binding to a chemokine receptor in an amount and under conditions such that fusion of HIV-1 to the CD4.sup.+ cells is inhibited, thereby inhibiting the HIV-1 infection. This invention provides non-chemokine agents capable of binding to the chemokine receptor and inhibiting fusion of HIV-1 to CD4.sup.+ cells. This invention also provides pharmaceutical compositions comprising an amount of the non-chemokine agent capable of binding to the chemokine receptor and inhibiting fusion of HIV-1 to CD4.sup.+ cells effective to prevent fusion of HIV-1 to CD4.sup.+ cells and a pharmaceutically acceptable carrier.

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Fayetteville, NY, United States of America

Virginia M Litwin