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In Vitro Assay to Evaluate the Impact of Immunoregulatory Pathways on HIV-specific CD4 T Cell Effector Function
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The CD4-mediated immune response is critical in determining the outcome of infection using Theiler's viruses with VP1

M Rodriguez1, R P Roos, D McGavern

  • 1Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA. rodriguez.moses@mayo.edu

Virology
|October 6, 2000
PubMed

Insights

CD4(+) T cells are crucial for clearing mutant Theiler's virus (DA) from the central nervous system (CNS), preventing demyelination in a multiple sclerosis model. Without these T cells, the virus persists and causes spinal cord damage.

Area of Science:

  • Immunology
  • Virology
  • Neuroscience

Background:

  • Theiler's virus (DA) infection in SJL mice models multiple sclerosis, causing chronic demyelination.
  • Mutations in the viral protein VP1 (at positions 99 or 100) attenuate DA's ability to cause disease.
  • The role of specific immune cells in clearing these mutant viruses was previously unclear.

Purpose of the Study:

  • To investigate the role of CD4(+) T cells in clearing VP1 mutant DA viruses from the CNS.
  • To determine the impact of CD4(+) T cell deficiency on demyelination and viral persistence.
  • To understand the immune mechanisms underlying the non-demyelinating phenotype of VP1 mutant DA viruses.

Main Methods:

  • Infection of CD4-deficient (CD4(-/-)) and CD8-deficient (CD8(-/-)) SJL mice with VP1 mutant DA viruses (DA-VP1-99(Ser) or DA-VP1-100(Asp)).
  • Assessment of viral persistence and demyelination in the spinal cord.
  • Analysis of virus-specific cytotoxicity in CNS-infiltrating lymphocytes.
  • Evaluation of neurovirulence in mice lacking the IFN-alpha/beta receptor.

Main Results:

  • CD4(-/-) mice infected with VP1 mutant DA viruses showed significant virus persistence and spinal cord demyelination.
  • CD8(-/-) mice infected with VP1 mutant DA viruses did not exhibit virus persistence or demyelination.
  • No virus-specific cytotoxicity was detected in CNS-infiltrating lymphocytes from infected SJL mice.
  • VP1 mutant viruses caused severe encephalitis and early death in IFN-alpha/beta receptor-deficient mice.

Conclusions:

  • CD4(+) T cells play a critical role in clearing VP1 mutant DA viruses from the CNS.
  • The non-demyelinating phenotype of VP1 mutant DA viruses is partly dependent on CD4-mediated immune responses.
  • These findings highlight the importance of CD4(+) T cell immunity in controlling viral persistence and preventing demyelination in this multiple sclerosis model.

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