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J Virol, June 1998, p. 4956-4961, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Entry of Amphotropic Murine Leukemia Virus Is Influenced by Residues in the Putative Second Extracellular Domain of Its Receptor, Pit2

Betsy D. Leverett,1 Karen B. Farrell,2 Maribeth V. Eiden,2 and Carolyn A. Wilson1,*

Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration,1 and Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, National Institutes of Health,2 Bethesda, Maryland

Received 9 September 1997/Accepted 2 March 1998

Human cells express distinct but related receptors for the gibbon ape leukemia virus (GALV) and the amphotropic murine leukemia virus (A-MuLV), termed Pit1 and Pit2, respectively. Pit1 is not able to function as a receptor for A-MuLV infection, while Pit2 does not confer susceptibility to GALV. Previous studies of chimeric receptors constructed by interchanging regions of Pit1 and Pit2 failed to clarify the determinants unique to Pit2 which correlate with A-MuLV receptor function. In order to identify which regions of Pit2 are involved in A-MuLV receptor function, we exchanged the putative second and third extracellular domains of Pit1, either individually or together, with the corresponding regions of Pit2. Our functional characterization of these receptors indicates a role for the putative second extracellular domain (domain II) in A-MuLV infection. We further investigated the influence of domain II with respect to A-MuLV receptor function by performing site-specific mutagenesis within this region of Pit2. Many of the mutations had little or no effect on receptor function. However, the substitution of serine for methionine at position 138 (S138M) in a Pit1 chimera containing domain II of Pit2 resulted in a 1,000-fold reduction in A-MuLV receptor function. Additional mutations made within domain II of the nonfunctional S138M mutant restored receptor function to nearly wild-type efficiency. The high degree of tolerance for mutations as well as the compensatory effect of particular substitutions observed within domain II suggests that an element of secondary structure within this region plays a critical role in the interaction of the receptor with A-MuLV.

* Corresponding author. Mailing address: FDA, CBER, HFM-530, 8800 Rockville Pike, Bethesda, MD 20892. Phone: (301) 827-0481. Fax: (301) 827-0449. E-mail: wilsonc{at}A1.cber.fda.gov.

J Virol, June 1998, p. 4956-4961, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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