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Journal of Virology, August 2005, p. 10776-10787, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10776-10787.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Caveola-Dependent Endocytic Entry of Amphotropic Murine Leukemia Virus

Christiane Beer,1,2 Ditte S. Andersen,1,{dagger} Aleksandra Rojek,3 and Lene Pedersen1,2*

Department of Molecular Biology,1 Institute of Clinical Medicine,2 Institute of Anatomy, Aarhus University, 8000 Aarhus C, Denmark3

Received 7 November 2004/ Accepted 24 May 2005

Early results suggested that the amphotropic murine leukemia virus (A-MLV) does not enter cells via endocytosis through clathrin-coated pits and this gammaretrovirus has therefore been anticipated to fuse directly with the plasma membrane. However, here we present data implicating a caveola-mediated endocytic entry route for A-MLV via its receptor Pit2. Caveolae belong to the cholesterol-rich microdomains characterized by resistance to nonionic detergents such as Triton X-100. Extraction of murine fibroblastic NIH 3T3 cells in cold Triton X-100 showed the presence of the A-MLV receptor Pit2 in detergent-insoluble microdomains. Using coimmunoprecipitation of cell extracts, we were able to demonstrate direct association of Pit2 with caveolin-1, the structural protein of caveolae. Other investigations revealed that A-MLV infection in contrast to vesicular stomatitis virus infection is a slow process (t {approx}5 h), which is dependent on plasma membrane cholesterol but independent of NH4Cl treatment of cells; NH4Cl impairs entry via clathrin-coated pits. Furthermore, expression of dominant-negative caveolin-1 decreased the susceptibility to infection via Pit2 by approximately 70%. These results show that A-MLV can enter cells via a caveola-dependent entry route. Moreover, increase in A-MLV infection by treatment with okadaic acid as well as entry of fusion-defective fluorescent A-MLV virions in NIH 3T3 cells further confirmed our findings and show that A-MLV can enter mouse fibroblasts via an endocytic entry route involving caveolae. Finally, we also found colocalization of fusion-defective fluorescent A-MLV virions with caveolin-1 in NIH 3T3 cells. This is the first time substantial evidence has been presented implicating the existence of a caveola-dependent endocytic entry pathway for a retrovirus.

* Corresponding author. Mailing address: Department of Molecular Biology, Aarhus University, C. F. Møllers Allé, Bldg. 130, DK-8000 Aarhus C, Denmark. Phone: 45-8942-2633. Fax: 45-8619-6500. E-mail: LP{at}mb.au.dk.

{dagger} Present address: Growth Regulation Laboratory, Cancer Research UK London Research Institute, London WC2A 3PX, United Kingdom.

Journal of Virology, August 2005, p. 10776-10787, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10776-10787.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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