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Herpesviruses in the Activated Phosphatidylinositol-3-Kinase-δ Syndrome

Jeffrey I Cohen1

  • 1Medical Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.

Frontiers in Immunology
|March 31, 2018
PubMed

Insights

Patients with overactive PI3K/Akt pathway signaling due to mutations experience lymphoproliferation and severe herpesvirus infections, including Epstein-Barr virus (EBV) and cytomegalovirus (CMV). This susceptibility is linked to altered CD8 T cell populations.

Area of Science:

  • Immunology
  • Virology
  • Genetics

Background:

  • The phosphatidylinositol-3-kinase (PI3K)/Akt pathway regulates critical stages of herpesvirus replication.
  • Gain-of-function mutations in PI3K subunits lead to constitutively active PI3K and hyperactivated Akt.
  • These genetic alterations are associated with lymphoproliferative disorders and increased susceptibility to viral infections.

Purpose of the Study:

  • To investigate the clinical manifestations and viral infection spectrum in patients with PI3K/Akt pathway hyperactivation.
  • To explore the immunological underpinnings of increased viral susceptibility in these patients.

Main Methods:

  • Clinical case review of patients with PI3K gain-of-function mutations.
  • Analysis of reported viral infections, focusing on herpesviruses like EBV and CMV.
  • Assessment of CD8 T cell populations (memory vs. terminally differentiated effector cells).

Main Results:

  • Patients exhibit lymphoproliferation and frequent, severe viral infections, notably Epstein-Barr virus (EBV) and cytomegalovirus (CMV).
  • Common presentations include persistent EBV/CMV viremia and EBV lymphoproliferative disease.
  • Reduced long-lived memory CD8 T cells and increased terminally differentiated effector CD8 T cells were observed.

Conclusions:

  • Constitutive PI3K/Akt activation due to specific mutations predisposes individuals to severe herpesvirus infections.
  • Altered CD8 T cell homeostasis contributes to impaired viral immunity in these patients.
  • Understanding this pathway is crucial for managing immune deficiencies and viral complications.
Keywords:
APDSAktEpstein–Barr virusPASLIPIK3CDPIK3R1cytomegalovirusphosphatidylinositol-3-kinase

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