Primary and Acquired Immunodeficiencies Associated With Severe Varicella-Zoster Virus Infections

Abstract

Background: Although most cases of varicella or zoster are self-limited, patients with certain immune deficiencies may develop severe or life-threatening disease.

Methods: We studied a patient with varicella-zoster virus (VZV) central nervous system (CNS) vasculopathy and as part of the evaluation, tested his plasma for antibodies to cytokines. We reviewed the literature for cases of varicella or zoster associated with primary and acquired immunodeficiencies.

Results: We found that a patient with VZV CNS vasculopathy had antibody that neutralized interferon (IFN)-α but not IFN-γ. The patient's plasma blocked phosphorylation in response to stimulation with IFN-α in healthy control peripheral blood mononuclear cells. In addition to acquired immunodeficiencies like human immunodeficiency virus (HIV) or autoantibodies to IFN, variants in specific genes have been associated with severe varicella and/or zoster. Although these genes encode proteins with very different activities, many affect IFN signaling pathways, either those that sense double-stranded RNA or cytoplasmic DNA that trigger IFN production, or those involved in activation of IFN stimulated genes in response to binding of IFN with its receptor.

Conclusions: Immune deficiencies highlight the critical role of IFN in control of VZV infections and suggest new approaches for treatment of VZV infection in patients with certain immune deficiencies.

Keywords: varicella-zoster; chickenpox; immunodeficiency; interferon; zoster.

Figure 1.

MRI and MRA findings in a man with VZV CNS vasculitis and neutralizing anti-interferon (IFN)-α antibodies. A, MRI of the spine shows ovoid lesions in T3–T4 (long arrows) and patchy lesions in T5–T11 (short arrows). B, MRI of the of brain shows left anteromedial thalamic enhancing lesion. C, MRA of the brain: arrow shows stenosis of right posterior cerebral artery. Abbreviations: CNS, central nervous system; IFN, interferon; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; VZV, varicella-zoster virus.

Figure 2.

Neutralizing anti-IFN-α antibodies in a man with VZV CNS vasculitis. A, Levels of serum antibodies to IFN-α and other cytokines. B, Control or patient PBMCs (5 × 10⁵ cells) were incubated with 10% healthy control or patient plasma and then stimulated with IFN-α (1000 U/mL) or IFN-γ (400 U/mL). PBMCs were fixed, permeabilized, stained for phospho-STAT-1, and analyzed by flow cytometry. STAT1 phosphorylation was induced by addition of IFN-α (red) or IFN-γ (blue) to (a) PBMCs from normal control with plasma from normal control (upper left), (b) PBMCs from the patient with plasma from normal control (upper right), (c) PBMCs from normal control with plasma from the patient (lower left), and (d) PBMCs from the patient with plasma from the patient (lower right). pSTAT1 was measured by flow cytometry. C, Level of plasma antibodies to IFN-α over time. See Supplementary Data for additional methods. Abbreviations: CNS, central nervous system; IFN, interferon; PBMCs, peripheral blood mononuclear cells; VZV, varicella-zoster virus.

Figure 3.

Sites at which proteins or antibodies associated with VZV diseases affect IFN signaling pathways. A, IFN binds to its receptor (IFNAR) which activates JAK and TYK2 resulting in phosphorylation of STATs, which translocate to the nucleus to activate ISGs. Antibody to IFN-α and proteins in which mutations are associated with severe VZV infections are indicated in red. B, Double-stranded RNA binds to TLR3, which activates TRIF, TRAF3, TBK1; and IRF3, which translocates to the nucleus to activate ISGs. C, AT-rich DNA is transcribed by RNA polymerase III resulting in 5′triphosphorylated RNA which activates RIG-I and results in IRF3 trafficking to the nucleus and activating ISGs. Abbreviations: IFN, interferon; ISG, interferon stimulated gene; PBMCs, peripheral blood mononuclear cells; VZV, varicella-zoster virus.