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.
Keywords:
APDS; Akt; Epstein–Barr virus; PASLI; PIK3CD; PIK3R1; cytomegalovirus; phosphatidylinositol-3-kinase.
Publication types
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Research Support, N.I.H., Intramural
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Review
MeSH terms
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Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors
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Class I Phosphatidylinositol 3-Kinases / drug effects
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Class I Phosphatidylinositol 3-Kinases / genetics
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Class I Phosphatidylinositol 3-Kinases / immunology*
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Class I Phosphatidylinositol 3-Kinases / metabolism
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Class Ia Phosphatidylinositol 3-Kinase
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Cytomegalovirus / immunology
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Cytomegalovirus / isolation & purification
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Cytomegalovirus Infections / drug therapy
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Cytomegalovirus Infections / genetics
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Cytomegalovirus Infections / immunology*
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Cytomegalovirus Infections / virology
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Epstein-Barr Virus Infections / drug therapy
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Epstein-Barr Virus Infections / genetics
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Epstein-Barr Virus Infections / immunology*
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Epstein-Barr Virus Infections / virology
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Gain of Function Mutation
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Genetic Predisposition to Disease
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Herpesvirus 4, Human / immunology
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Herpesvirus 4, Human / isolation & purification
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Humans
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Immunologic Deficiency Syndromes / genetics
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Immunologic Deficiency Syndromes / immunology*
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Immunologic Deficiency Syndromes / virology
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Immunosuppressive Agents / pharmacology
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Immunosuppressive Agents / therapeutic use
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / immunology*
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Phosphatidylinositol 3-Kinases / metabolism
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Primary Immunodeficiency Diseases
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Proto-Oncogene Proteins c-akt / immunology
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Proto-Oncogene Proteins c-akt / metabolism
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Viremia / drug therapy
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Viremia / genetics
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Viremia / immunology*
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Viremia / virology
Substances
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Immunosuppressive Agents
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PIK3R1 protein, human
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Class I Phosphatidylinositol 3-Kinases
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Class Ia Phosphatidylinositol 3-Kinase
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PIK3CD protein, human
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Proto-Oncogene Proteins c-akt
Supplementary concepts
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Activated PI3K-delta Syndrome