Multiple defects, including premature apoptosis, prevent Kaposi's sarcoma-associated herpesvirus replication in...

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Kaposi's sarcoma-associated herpesvirus (KSHV) infection is challenging to model in mice due to limited host range.
• Understanding KSHV host range restriction is crucial for developing effective therapeutic strategies.
• Previous studies indicate KSHV efficiently enters murine cells but fails to produce infectious virions.

Purpose of the Study:

• To investigate the molecular mechanisms underlying KSHV host range restriction in murine cells.
• To identify cellular factors and viral processes that impede lytic KSHV replication in mice.

Main Methods:

• Ectopic expression of KSHV RTA (replication and transcription activator) in murine cells.
• Treatment of KSHV-infected murine cells with histone deacetylase inhibitors.
• Genetic ablation of the mitochondrial apoptotic pathway in KSHV-infected murine cells.
• Assessment of viral gene expression, DNA synthesis, and virion production.

Main Results:

• Ectopic RTA expression resulted in limited viral gene expression and no virus production.
• Histone deacetylase inhibitors induced aberrant viral transcription but not viral DNA synthesis or virion production.
• Enhanced apoptosis was observed in aberrantly infected murine cells.
• Ablation of the mitochondrial apoptotic pathway allowed viral DNA replication but not virion production.

Conclusions:

• Multiple defects, occurring both before and after viral DNA synthesis, restrict lytic KSHV infection in murine cells.
• Apoptosis plays a significant role in limiting KSHV replication in mice.
• A mouse model for KSHV infection requires overcoming several barriers beyond initial entry and latency establishment.