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Preferential Targeting of CD4-CCR5 Complexes with Bifunctional Inhibitors: A Novel Approach to Block HIV-1 Infection¹

Matthias Mack^2,*, Jochen Pfirstinger^*, Jürgen Haas, Peter J. Nelson, Peter Kufer, Gert Riethmüller and Detlef Schlöndorff

^* Klinikum, University of Regensburg, Regensburg, Germany; Max von Pettenkofer Institute, University of Munich, Munich, Germany; Medical Policlinic, University of Munich, Munich, Germany; and Institute of Immunology, University of Munich, Munich, Germany

Two receptors, CD4 and one of several chemokine receptors, are required for cellular HIV-1 infection, with CCR5 being the main coreceptor for macrophage-tropic strains. We have designed bifunctional fusion proteins, consisting of RANTES/CCL5 and a single-chain Fv Ab fragment against CD4 to simultaneously block CD4 and CCR5. The fusion proteins bind to both receptors, compete with RANTES/CCL5 binding, and induce down-modulation of CCR5 10 times more efficiently on CD4⁺ compared with CD8⁺ T cells. Moreover, after short incubation and subsequent washout, a significant down-modulation of CCR5 was only seen with the fusion proteins and only on CD4⁺ cells, but not with unmodified RANTES or on CD4^– cells, indicating a preferential targeting of CCR5 on CD4⁺ T cells. The fusion proteins block M-tropic HIV infection more efficiently than RANTES/CCL5 and CD4 Abs alone or in combination. To our knowledge this is the first report of simultaneous blockade of an HIV-1 receptor and coreceptor with bifunctional inhibitors.

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