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

Jeffrey I. Cohen

doi:10.3389/fimmu.2018.00237

Abstract

The phosphatidylinositol-3-kinase (PI3K)/Akt pathway is important for multiple stages of herpesvirus replication including virus entry, replication, latency, and reactivation. Recently, patients with gain-of-function mutations in the p110δ-catalytic subunit of PI3K or in the p85-regulatory subunit of PI3K have been reported. These patients have constitutively active PI3K with hyperactivation of Akt. They present with lymphoproliferation and often have infections, particularly recurrent respiratory infections and/or severe virus infections. The most frequent virus infections are due to Epstein–Barr virus (EBV) and cytomegalovirus (CMV); patients often present with persistent EBV and/or CMV viremia, EBV lymphoproliferative disease, or CMV lymphadenitis. No patients have been reported with CMV pneumonia, colitis, or retinitis. Other herpesvirus infections have included herpes simplex pneumonia, recurrent zoster, and varicella after vaccination with the varicella vaccine. Additional viral infections have included adenovirus viremia, severe warts, and extensive Molluscum contagiosum virus infection. The increased susceptibility to virus infections in these patients is likely due to a reduced number of long-lived memory CD8 T cells and an increased number of terminally differentiated effector CD8 T cells.

Highlights

Viruses often exploit intracellular signaling pathways to facilitate entry, replication, latency, and reactivation
Class I PI3K complexes are important for virus infection and consist of a regulatory subunit (p50, p55, or p85) and a catalytic subunit (p110α, β, γ, or δ)
Mutations in the p85-regulatory subunit or the p110δ-catalytic subunit have been associated with immunodeficiencies often presenting with lymphoproliferative disease, recurrent respiratory infections, and severe herpesvirus infections

Summary

INTRODUCTION

Viruses often exploit intracellular signaling pathways to facilitate entry, replication, latency, and reactivation. While it is possible that chronic infection with CMV or EBV could have resulted in the observed senescence of CD8 T cells, there was no correlation with the EBV and CMV load in the blood and the number of senescent CD8 T cells Since these two reports were published, additional papers have reported persistent herpesvirus viremia or severe herpesvirus infections in patients with PIK3CD gain-of-function mutations (Table 1). In the first report of patients with gain-of-function PIK3R1 mutations, Deau et al [31] described four patients with recurrent respiratory bacterial infections, two of whom had EBV viremia and one of whom had both CMV and EBV viremia (9,300 and 1,500 copies/ml, respectively). Angulo Lucas Crank Hartman Kannan Lawrence Elgizouli Dulau Florea et al [29] et al [30] et al [34] et al [35] et al [36] et al [37] et al [38] et al [39]b

17 E1021K

Findings

Splice donor-site mutations resulting in loss of exon 11