The chemokine receptors CCR5 and CXCR4 belong to the family of seven transmembrane-span ning G protein-coupled receptors, which have diverse functions in host cell defense and are associated with numerous diseases. CCR5 and CXCR4 are known as co-receptors for entry of HIV-1. In this study the intracellular carboxy-terminus of CCR5, which is deleted in HIV-infected longterm non-progressors, was shown to interact with the carboxy-terminus of a-catenin, a component of the cytoskeleton, in a yeast two-hybrid screen. This interaction was verified in mammalian cells. Furthermore, the interaction of alpha-catenin with CCR5 and CXCR4 at endogenous protein levels was demonstrated in PM1 T-lymphocytes, a host cell line of HIV-1. Our results suggest that a-catenin links CCR5 and CXCR4 to the cytoskeleton and is involved in the organization of these receptors at the membrane, thereby possibly affecting HIV-1 infection. (C) 2004 Elsevier Inc. All rights reserved.