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J Virol, June 1998, p. 4746-4755, Vol. 72, No. 6
Department of Microbiology and Institute for
Cellular and Molecular Biology, The University of Texas at Austin,
Austin, Texas 78712,1 and
The University
of Texas M. D. Anderson Cancer Center, Bastrop, Texas
786022
Received 13 November 1997/Accepted 10 February 1998
The mouse mammary tumor virus (MMTV) encodes within the U3 region
of the long terminal repeat (LTR) a protein known as the superantigen
(Sag). Sag is needed for the efficient transmission of milk-borne virus
from the gut to target tissue in the mammary gland. MMTV-infected B
cells in the gut express Sag as a type II transmembrane protein that is
recognized by the variable region of particular beta chains (V
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Mutational and Functional Analysis of the C-Terminal Region of
the C3H Mouse Mammary Tumor Virus Superantigen
) of
the T-cell receptor (TCR) on the surface of T cells. Recognition of Sag
by particular TCRs results in T-cell stimulation, release of cytokines,
and amplification of MMTV infection in lymphoid cells that are needed
for infection of adolescent mammary tissue. Because the C-terminal 30 to 40 amino acids of Sag are variable and correlate with recognition of
particular TCR V chains, we prepared a series of C-terminal Sag
mutations that were introduced into a cloned infectious MMTV provirus.
Virus-producing XC rat cells were used for injection of susceptible
BALB/c mice, and these mice were monitored for functional Sag activity
by the deletion of C3H MMTV Sag-reactive (CD4+
V14+) T cells. Injected mice also were analyzed for
mutant infection and tumor formation in mammary glands as well as
milk-borne transmission of MMTV to offspring. Most mutations abrogated
Sag function, although one mutation (HPA242) that changed the negative
charge of the extreme C terminus to a positive charge created a weaker
Sag that slowed the kinetics of Sag-mediated T-cell deletion. Despite
the lack of Sag activity, many of the sag mutant viruses
were capable of sporadic infections of the mammary glands of injected
mice but not of offspring mice, indicating that functional Sag
increases the probability of milk-borne MMTV infection. Furthermore,
although most viruses encoding nonfunctional Sags were unable to cause mammary tumors, tumors were induced by such viruses carrying mutations in a negative regulatory element that overlaps the sag gene
within the LTR, suggesting that loss of Sag function may be
compensated, at least partially, by loss of transcriptional suppression
in certain tissues. Together these results confirm the importance of
Sag for efficient milk-borne transmission and indicate that the entire
C-terminal region is needed for complete Sag function.
*
Corresponding author. Mailing address: Department of
Microbiology and Institute for Cellular and Molecular Biology, The
University of Texas at Austin, Austin, TX 78712. Phone: (512) 471-8415. Fax: (512) 471-7088. E-mail:
jdudley{at}uts.cc.utexas.edu.
Present address: Arnold, White & Durkee, Austin, Tex.
J Virol, June 1998, p. 4746-4755, Vol. 72, No. 6
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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