Phosphoinositide 3'-Kinase γ Facilitates Polyomavirus Infection

Area of Science:

• Virology
• Cell Biology
• Molecular Biology

Background:

• Polyomaviruses cause severe diseases, like progressive multifocal leukoencephalopathy (PML), in immunocompromised individuals.
• The specific molecular mechanisms of polyomavirus entry into host cells remain largely unknown.

Purpose of the Study:

• To identify cellular factors involved in the entry and infection process of polyomaviruses, particularly the JC polyomavirus (JCPyV).
• To investigate the role of phosphoinositide 3'-kinases (PI3Ks) in facilitating JCPyV infection.

Main Methods:

• Genetic knockdown and CRISPR/Cas9 gene knockout were used to assess the function of PI3K isoforms and PIK3R5 in human glial cells.
• Infection assays were performed using authentic JCPyV, pseudoviruses (JCPyV, BK, Merkel Cell), and simian virus 40 (SV40).
• Reintroduction of the PI3Kγ gene was used to confirm its role in rescuing infection defects.

Main Results:

• Phosphoinositide 3'-kinase gamma (PI3Kγ) and its regulatory subunit PIK3R5 were identified as essential for JCPyV infection in SVG-A glial cells.
• Knockout of PIK3R5 or PI3Kγ significantly inhibited infection by JCPyV, BK, Merkel Cell polyomaviruses, and SV40.
• PI3Kγ disruption did not affect virus binding or internalization, indicating a role in intracellular post-entry steps.

Conclusions:

• PI3Kγ and PIK3R5 are critical cellular factors supporting intracellular stages of polyomavirus infection.
• Targeting PI3Kγ signaling pathways presents a potential therapeutic avenue for managing polyomavirus infections.