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Journal of Virology, January 2006, p. 353-359, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.353-359.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Expanded Tropism and Altered Activation of a Retroviral Glycoprotein Resistant to an Entry Inhibitor Peptide

Sean M. Amberg,{dagger} Robert C. Netter, Graham Simmons, and Paul Bates*

Department of Microbiology, University of Pennsylvania School of Medicine, 225 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, Pennsylvania 19104-6076

Received 4 May 2005/ Accepted 9 October 2005

The envelope of class I viruses can be a target for potent viral inhibitors, such as the human immunodeficiency virus type 1 (HIV-1) inhibitor enfuvirtide, which are derived from the C-terminal heptad repeat (HR2) of the transmembrane (TM) subunit. Resistance to an HR2-based peptide inhibitor of a model retrovirus, subgroup A of the Avian Sarcoma and Leukosis Virus genus (ASLV-A), was studied by examining mutants derived by viral passage in the presence of inhibitor. Variants with reduced sensitivity to inhibitor were readily selected in vitro. Sensitivity determinants were identified for 13 different isolates, all of which mapped to the TM subunit. These determinants were identified in two regions: (i) the N-terminal heptad repeat (HR1) and (ii) the N-terminal segment of TM, between the subunit cleavage site and the fusion peptide. The latter class of mutants identified a region outside of the predicted HR2-binding site that can significantly alter sensitivity to inhibitor. A subset of the HR1 mutants displayed the unanticipated ability to infect nonavian cells. This expanded tropism was associated with increased efficiency of envelope triggering by soluble receptor at low temperatures, as measured by protease sensitivity of the surface subunit (SU) of envelope. In addition, expanded tropism was linked for the most readily triggered mutants with increased sensitivity to neutralization by SU-specific antiserum. These observations depict a class of HR2 peptide-selected mutations with a reduced activation threshold, thereby allowing the utilization of alternative receptors for viral entry.

* Corresponding author. Mailing address: Department of Microbiology, University of Pennsylvania School of Medicine, 225 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104-6076. Phone: (215) 573-3509. Fax: (215) 573-9068. E-mail: pbates{at}mail.med.upenn.edu.

{dagger} Present address: SIGA Technologies, Inc., Corvallis, OR.

Journal of Virology, January 2006, p. 353-359, Vol. 80, No. 1
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.1.353-359.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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