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

Abstract

Varicella-zoster virus (VZV) is a human neurotropic alphaherpesvirus and the etiological agent of varicella (chickenpox) and herpes zoster (HZ, shingles). Previously, inoculation of monkeys via the subcutaneous, intratracheal, intravenous, or oral-nasalconjunctival routes did not recapitulate all the hallmarks of VZV infection, including varicella, immunity, latency, and reactivation. Intrabronchial inoculation of rhesus macaques (RMs) with simian varicella virus (SVV), a homolog of VZV, recapitulates virologic and immunologic hallmarks of VZV infection in humans. Given that VZV is acquired primarily via the respiratory route, we investigated whether intrabronchial inoculation of RMs with VZV would result in a robust model. Despite the lack of varicella and viral replication in either the lungs or whole blood, all four RMs generated an immune response characterized by the generation of VZV-specific antibodies and T cells. Two of 4 VZV-inoculated RMs were challenged with SVV to determine cross-protection. VZV-immune RMs displayed no varicella rash and had lower SVV viral loads and earlier and stronger humoral and cellular immune responses than controls. In contrast to the results for SVV DNA, no VZV DNA was detected in sensory ganglia at necropsy. In summary, following an abortive VZV infection, RMs developed an adaptive immune response that conferred partial protection against SVV challenge. These data suggest that a replication-incompetent VZV vaccine that does not establish latency may provide sufficient protection against VZV disease and that VZV vaccination of RMs followed by SVV challenge provides a model to evaluate new vaccines and therapeutics against VZV. IMPORTANCEAlthough VZV vaccine strain Oka is attenuated, it can cause mild varicella, establish latency, and in rare cases, reactivate to cause herpes zoster (HZ). Moreover, studies suggest that the HZ vaccine (Zostavax) only confers short-lived immunity. The development of more efficacious vaccines would be facilitated by a robust animal model of VZV infection. The data presented in this report show that intrabronchial inoculation of rhesus macaques (RMs) with VZV resulted in an abortive VZV infection. Nevertheless, all animals generated a humoral and cellular immune response that conferred partial cross-protection against simian varicella virus (SVV) challenge. Additionally, VZV DNA was not detected in the sensory ganglia, suggesting that viremia might be required for the establishment of latency. Therefore, VZV vaccination of RMs followed by SVV challenge is a model that will support the development of vaccines that boost protective T cell responses against VZV. V aricella-zoster virus (VZV), a neurotropic alphaherpesvirus, is the etiologic agent of varicella (chickenpox) and herpes zoster (HZ, shingles). Primary VZV infection likely occurs through inhalation of virus either in respiratory droplets (1, 2) or from shedding varicella lesions (3) or through direct contact with infectious vesicular fluid (4). VZV establishes latency in sensory ...

Varicella Zoster Virus in the Nervous System

“…In intradermally inoculated guinea pigs, VZV nucleic acids and proteins were still found in enteric ganglia, stomach, ileum, and colon of guinea pigs 1 month later 39 . In non-human primates, experimental inoculation of VZV produced a humoral and cell-mediated immune response, but the virus did not become latent in ganglia 40 .…”

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.…”

Reactivation of Simian Varicella Virus in Rhesus Macaques after CD4 T Cell Depletion

“…Inoculation of VZV into small animals, including mice (15), guinea pigs (16)(17)(18)(19), and rats (20,21), does not mimic all the features of primary VZV infection or latency seen in humans, although virus DNA can be found in ganglia. Inoculation of monkeys with VZV produces immune responses without clinical symptoms and does not establish latency in ganglia (22,23). Importantly, VZV cannot be reactivated in any of these models.…”