Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence

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Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence

R Ahmed, A Salmi, LD Butler, JM Chiller and MB Oldstone

We studied the mechanism of lymphocytic choriomeningitis virus (LCMV) persistence and the suppression of cytotoxic T lymphocyte (CTL) responses in BALB/c WEHI mice infected at birth with LCMV Armstrong strain. Using adoptive transfer experiments we found that spleen cells from persistently infected (carrier) mice actively suppressed the expected LCMV-specific CTL response of spleen cells from normal adult mice. The suppression was specific for the CTL response and LCMV - specific antibody responses were not affected. Associated with the specific CTL suppression was the establishment of persistent LCMV infection. The transfer of spleen or lymph node cells containing LCMV - specific CTL resulted in virus clearance and prevented establishment of the carrier state. The suppression of LCMV -specific CTL responses by carrier spleen cells is not mediated by a suppressor cell, but is due to the presence of genetic variants of LCMV in spleens of carrier mice. Such virus variants selectively suppress LCMV-specific CTL responses and cause persistent infections in immunocompetent mice. In striking contrast, wild-type LCMV Armstrong, from which these variants were generated, induces a potent CTL response in immunocompetent mice and the LCMV infection is rapidly cleared. Our results show that LCMV variants that emerge during infection in vivo play a crucial role in the suppression of virus-specific CTL responses and in the maintenance of virus persistence.
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Suresh, M., Whitmire, J. K., Harrington, L. E., Larsen, C. P., Pearson, T. C., Altman, J. D., Ahmed, R. (2001). Role of CD28-B7 Interactions in Generation and Maintenance of CD8 T Cell Memory. J. Immunol. 167: 5565-5573 [Abstract] [Full Text]
Williams, M. A., Tan, J. T., Adams, A. B., Durham, M. M., Shirasugi, N., Whitmire, J. K., Harrington, L. E., Ahmed, R., Pearson, T. C., Larsen, C. P. (2001). Characterization of Virus-Mediated Inhibition of Mixed Chimerism and Allospecific Tolerance. J. Immunol. 167: 4987-4995 [Abstract] [Full Text]
Wu-Hsieh, B. A., Whitmire, J. K., de Fries, R., Lin, J.-S., Matloubian, M., Ahmed, R. (2001). Distinct CD8 T Cell Functions Mediate Susceptibility to Histoplasmosis During Chronic Viral Infection. J. Immunol. 167: 4566-4573 [Abstract] [Full Text]
Ou, R., Zhou, S., Huang, L., Moskophidis, D. (2001). Critical Role for Alpha/Beta and Gamma Interferons in Persistence of Lymphocytic Choriomeningitis Virus by Clonal Exhaustion of Cytotoxic T Cells. J. Virol. 75: 8407-8423 [Abstract] [Full Text]
Grayson, J. M., Lanier, J. G., Altman, J. D., Ahmed, R. (2001). The Role of p53 in Regulating Antiviral T Cell Responses. J. Immunol. 167: 1333-1337 [Abstract] [Full Text]