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Journal of Virology, March 2003, p. 3058-3066, Vol. 77, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.5.3058-3066.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Avian Retrovirus Avian Sarcoma/Leukosis Virus Subtype A Reaches the Lipid Mixing Stage of Fusion at Neutral pH

Laurie J. Earp,1 Sue E. Delos,2 Robert C. Netter,3 Paul Bates,3 and Judith M. White1*

Department of Microbiology,1 Department of Cell Biology, University of Virginia, Charlottesville, Virginia 22908,2 Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 191043

Received 17 June 2002/ Accepted 5 December 2002

We previously showed that the envelope glycoprotein (EnvA) of avian sarcoma/leukosis virus subtype A (ASLV-A) binds to liposomes at neutral pH following incubation with its receptor, Tva, at >=22°C. We also provided evidence that ASLV-C fuses with cells at neutral pH. These findings suggested that receptor binding at neutral pH and >=22°C is sufficient to activate Env for fusion. A recent study suggested that two steps are necessary to activate avian retroviral Envs: receptor binding at neutral pH, followed by exposure to low pH (W. Mothes et al., Cell 103:679-689, 2000). Therefore, we evaluated the requirements for intact ASLV-A particles to bind to target bilayers and fuse with cells. We found that ASLV-A particles bind stably to liposomes in a receptor- and temperature-dependent manner at neutral pH. Using ASLV-A particles biosynthetically labeled with pyrene, we found that ASLV-A mixes its lipid envelope with cells within 5 to 10 min at 37°C. Lipid mixing was neither inhibited nor enhanced by incubation at low pH. Lipid mixing of ASLV-A was inhibited by a peptide designed to prevent six-helix bundle formation in EnvA; the same peptide inhibits virus infection and EnvA-mediated cell-cell fusion (at both neutral and low pHs). Bafilomycin and dominant-negative dynamin inhibited lipid mixing of Sindbis virus (which requires low pH for fusion), but not of ASLV-A, with host cells. Finally, we found that, although EnvA-induced cell-cell fusion is enhanced at low pH, a mutant EnvA that is severely compromised in its ability to support infection still induced massive syncytia at low pH. Our results indicate that receptor binding at neutral pH is sufficient to activate EnvA, such that ASLV-A particles bind hydrophobically to and merge their membranes with target cells. Possible roles for low pH at subsequent stages of viral entry are discussed.

* Corresponding author. Mailing address: Department of Cell Biology, UVA Health System, School of Medicine, P.O. Box 800732, Charlottesville, VA 22908-0732. Phone: (434) 924-2593. Fax: (434) 982-3912. E-mail: jw7g{at}virginia.edu.

Journal of Virology, March 2003, p. 3058-3066, Vol. 77, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.5.3058-3066.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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