CD4 T Cell Immunity Is Critical for the Control of Simian Varicella Virus Infection in a Nonhuman Primate Model of VZV Infection

Abstract

Primary infection with varicella zoster virus (VZV) results in varicella (more commonly known as chickenpox) after which VZV establishes latency in sensory ganglia. VZV can reactivate to cause herpes zoster (shingles), a debilitating disease that affects one million individuals in the US alone annually. Current vaccines against varicella (Varivax) and herpes zoster (Zostavax) are not 100% efficacious. Specifically, studies have shown that 1 dose of varivax can lead to breakthrough varicella, albeit rarely, in children and a 2-dose regimen is now recommended. Similarly, although Zostavax results in a 50% reduction in HZ cases, a significant number of recipients remain at risk. To design more efficacious vaccines, we need a better understanding of the immune response to VZV. Clinical observations suggest that T cell immunity plays a more critical role in the protection against VZV primary infection and reactivation. However, no studies to date have directly tested this hypothesis due to the scarcity of animal models that recapitulate the immune response to VZV. We have recently shown that SVV infection of rhesus macaques models the hallmarks of primary VZV infection in children. In this study, we used this model to experimentally determine the role of CD4, CD8 and B cell responses in the resolution of primary SVV infection in unvaccinated animals. Data presented in this manuscript show that while CD20 depletion leads to a significant delay and decrease in the antibody response to SVV, loss of B cells does not alter the severity of varicella or the kinetics/magnitude of the T cell response. Loss of CD8 T cells resulted in slightly higher viral loads and prolonged viremia. In contrast, CD4 depletion led to higher viral loads, prolonged viremia and disseminated varicella. CD4 depleted animals also had delayed and reduced antibody and CD8 T cell responses. These results are similar to clinical observations that children with agammaglobulinemia have uncomplicated varicella whereas children with T cell deficiencies are at increased risk of progressive varicella with significant complications. Moreover, our studies indicate that CD4 T cell responses to SVV play a more critical role than antibody or CD8 T cell responses in the control of primary SVV infection and suggest that one potential mechanism for enhancing the efficacy of VZV vaccines is by eliciting robust CD4 T cell responses.

Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques

“…JAK inhibitor (tofacitinib citrate, CP-690550 citrate; Selleckchem, Houston, TX, USA) at 15 mg/kg diluted in 0Á5% methylcellulose was given for 5 consecutive days by oral gavage [29]. Each cohort consisted of four animals, which is the minimum number of animals needed to achieve sufficient power to detect a statistically significant difference in various immunological parameters following SVV infection [37,[56][57][58][59]. The necropsy schedules were based on the return of white blood cell (WBC) counts to baseline levels and the cessation of lymphocyte proliferation.…”

Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity

“…Like all herpes viruses, VZV enters latency, with sensory ganglia serving as reservoirs. The virus is kept dormant by intact antiviral immunity, specifically virus-specific CD4 T cells (3). In the general population, the lifetime risk for developing viral reactivation presenting as the typically painful, blistering dermatomal rash is estimated to be approximately 30% to 50%, with a sharp increase in incidence after the age of 50 years (4).…”

Abortive Intrabronchial Infection of Rhesus Macaques with Varicella-Zoster Virus Provides Partial Protection against Simian Varicella Virus Challenge

“…Therefore, we challenged two of the VZV-inoculated animals intrabronchially with a dose of live SVV that consistently results in clinical disease and viremia in rhesus macaques (68,83,84). Our data demonstrate that a replication-deficient-virus vaccination provides complete protection against clinical symptoms and partial protection against viral replication following a rigorous live-virus challenge and, therefore, merits further investigation.…”