A variety of human viruses, including herpes viruses, hepatitis B virus and HIV, produce acute infections followed by persistence or recrudescence. However, the mechanism(s) regulating persistence and recrudescence depend on a balance between viral replication and the host immune response. Viral tropism and antigenic load provide additional determinants in this complex scheme. This proposal examines the contribution of cell mediated and humoral immunity in controlling recrudescence of a neurotropic virus following initial clearance. Infection of immunocompetent mice induces an acute encephalomyelitis, followed by persistence without infectious virus. During acute infection cell mediated immunity, predominantly the CD8+ T cells, are crucial in controlling virus replication within the central nervous system (CNS). However, in the absence of B cells, these effector functions do not suffice to suppress virus to undetectable levels, thereby allowing virus reactivation. Importantly, transfer of anti-viral antibody (Ab) prevents virus reactivation, implicating a crucial role for Ab and/or B cells in controlling persistence. However, analysis of virus specific T cells using class I tetramet technology revealed that the percentage of virus specific CD8+ T cells in the CNS is reduced compared to immunocompetent mice. In addition, there is no increase in virus specific T cells during reactivation. These data suggested that CD8+ T cells may be functionally impaired or exhausted due to increased antigen load. This proposal distinguishes between the requirement(s) for potent CD8+ T cell function vs Ab in controlling virus reactivation in a persistently infected host. The contribution of both neutralizing and non neutralizing Ab, Fc receptor (FcR) activity and complement are examined by Ab transfers and using mice deficient in FeR. These experiments will determine the mechanism of Ab mediated prevention of virus reactivation in an Ab deficient milieu. The possibility that the absence of Ab and/or B cells results in defective CD8+ T cell priming, ultimately leading to exhaustion during recrudescence is tested by functional and phenotypic analysis of CD8+ T cells during priming and recrudescence. Intervention via transfer of protective Ab or CD8+ T cells activated in vitro will determine if functionally impaired CD8+ T cells can be overcome. These experiments may have direct implications for therapeutic interventions during persistent viral infections. Finally, virus reactivation will be tested in an Ab deficient mouse with a normal B cell compartment. These experiments will distinguish between the possibilities of an Ab independent effect of B cells and a CD8+ T cell defect related to the absence of B cells. This proposal will provide insight into the immunological regulation of both virus recrudescence and the CNS as a target organ.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology Study Section (VR)
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Park, Eun-Chung
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University of Southern California
Schools of Medicine
Los Angeles
United States
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Phares, Timothy W; DiSano, Krista D; Stohlman, Stephen A et al. (2014) Progression from IgD+ IgM+ to isotype-switched B cells is site specific during coronavirus-induced encephalomyelitis. J Virol 88:8853-67
Phares, Timothy W; Stohlman, Stephen A; Hinton, David R et al. (2013) Astrocyte-derived CXCL10 drives accumulation of antibody-secreting cells in the central nervous system during viral encephalomyelitis. J Virol 87:3382-92
Phares, Timothy W; Stohlman, Stephen A; Bergmann, Cornelia C (2013) Intrathecal humoral immunity to encephalitic RNA viruses. Viruses 5:732-52
Phares, Timothy W; DiSano, Krista D; Hinton, David R et al. (2013) IL-21 optimizes T cell and humoral responses in the central nervous system during viral encephalitis. J Neuroimmunol 263:43-54
Phares, Timothy W; Stohlman, Stephen A; Hwang, Mihyun et al. (2012) CD4 T cells promote CD8 T cell immunity at the priming and effector site during viral encephalitis. J Virol 86:2416-27
Phares, Timothy W; Stohlman, Stephen A; Hinton, David R et al. (2012) Enhanced CD8 T-cell anti-viral function and clinical disease in B7-H1-deficient mice requires CD4 T cells during encephalomyelitis. J Neuroinflammation 9:269
Phares, Timothy W; Marques, Cristina P; Stohlman, Stephen A et al. (2011) Factors supporting intrathecal humoral responses following viral encephalomyelitis. J Virol 85:2589-98
Marques, Cristina P; Kapil, Parul; Hinton, David R et al. (2011) CXCR3-dependent plasma blast migration to the central nervous system during viral encephalomyelitis. J Virol 85:6136-47
Parra, Gabriel I; Bergmann, Cornelia C; Phares, Timothy W et al. (2010) Gamma interferon signaling in oligodendrocytes is critical for protection from neurotropic coronavirus infection. J Virol 84:3111-5
Phares, Timothy W; Stohlman, Stephen A; Hinton, David R et al. (2010) Enhanced antiviral T cell function in the absence of B7-H1 is insufficient to prevent persistence but exacerbates axonal bystander damage during viral encephalomyelitis. J Immunol 185:5607-18

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