Infected cell protein (ICP)47 enhances herpes simplex virus neurovirulence by blocking the CD8+ T cell response

Area of Science:

• Immunology
• Virology
• Neuroscience

Background:

• Herpes simplex virus (HSV) establishes lifelong infections in neurons.
• HSV infected cell protein 47 (ICP47) is known to inhibit the transporter associated with antigen presentation (TAP), thus blocking CD8+ T cell recognition of infected cells.
• Understanding viral mechanisms that evade immune responses is crucial for controlling HSV infections.

Purpose of the Study:

• To investigate the role of HSV-1 ICP47 in viral neurovirulence.
• To determine if ICP47's inhibition of the transporter associated with antigen presentation (TAP) pathway impacts CD8+ T cell-mediated protection against HSV-1 neuroinvasion.

Main Methods:

• Generation and characterization of an HSV-1 ICP47-mutant virus.
• Comparative neurovirulence studies in mice, including immunologically normal, T cell-deficient (nude), and CD8+ T cell-depleted or CD4+ T cell-reconstituted mice.
• Assessment of viral replication in epithelial tissues and the nervous system.

Main Results:

• The HSV-1 ICP47-mutant exhibited significantly reduced neurovirulence compared to wild-type HSV-1 in immunocompetent mice.
• Reduced neurovirulence of the ICP47-mutant was dependent on CD8+ T cells, as demonstrated in reconstituted nude mice and CD8+ T cell-depleted mice.
• The ICP47-mutant replicated normally in epithelial tissues, indicating its role is specific to neurovirulence.
• CD8+ T cell depletion did not affect the neurovirulence of an unrelated attenuated HSV-1 mutant, highlighting ICP47's specific mechanism.

Conclusions:

• HSV-1 ICP47 plays a critical role in promoting neurovirulence by evading CD8+ T cell surveillance.
• ICP47 is the first viral protein identified to influence neurovirulence through the inhibition of CD8+ T cell-mediated protection.
• Targeting ICP47 or enhancing CD8+ T cell responses could be potential strategies for managing HSV neurological infections.