Simian Varicella Virus Infection of Rhesus Macaques Recapitulates Essential Features of Varicella Zoster Virus Infection in Humans

Abstract

Simian varicella virus (SVV), the etiologic agent of naturally occurring varicella in primates, is genetically and antigenically closely related to human varicella zoster virus (VZV). Early attempts to develop a model of VZV pathogenesis and latency in nonhuman primates (NHP) resulted in persistent infection. More recent models successfully produced latency; however, only a minority of monkeys became viremic and seroconverted. Thus, previous NHP models were not ideally suited to analyze the immune response to SVV during acute infection and the transition to latency. Here, we show for the first time that intrabronchial inoculation of rhesus macaques with SVV closely mimics naturally occurring varicella (chickenpox) in humans. Infected monkeys developed varicella and viremia that resolved 21 days after infection. Months later, viral DNA was detected only in ganglia and not in non-ganglionic tissues. Like VZV latency in human ganglia, transcripts corresponding to SVV ORFs 21, 62, 63 and 66, but not ORF 40, were detected by RT-PCR. In addition, as described for VZV, SVV ORF 63 protein was detected in the cytoplasm of neurons in latently infected monkey ganglia by immunohistochemistry. We also present the first in depth analysis of the immune response to SVV. Infected animals produced a strong humoral and cell-mediated immune response to SVV, as assessed by immunohistology, serology and flow cytometry. Intrabronchial inoculation of rhesus macaques with SVV provides a novel model to analyze viral and immunological mechanisms of VZV latency and reactivation.

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

“…RMs (Macaca mulatta) were infected intrabronchially with 4 3 10 5 plaque-forming units (PFU) of wild-type simian varicella virus (SVV) in the form of intact infected telomerized rhesus fibroblasts. Peripheral blood mononuclear cells (PBMC) and bronchoalveolar lavage (BAL) cells were collected from RMs as described previously [37].…”

“…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.…”

“…SVV DNA viral loads in WB and BAL cells were measured by qPCR using Maxima Probe/ROX qPCR Master Mix (32) (Fermentas, Glen Burnie, MD, USA) and primers/Taqman probe specific for SVV ORF21 [37]. Following an initial 10-min 958C step, 40 cycles of 15 s at 958C and 1 min at 608C were completed using StepOnePlus (Life Technologies, Carlsbad, CA, USA).…”

“…Intrabronchial infection of rhesus macaques with SVV, a homologue of varicella zoster virus (VZV), recapitulates the hallmarks of VZV infection in humans [37]. Reactivation of VZV is a frequent complication of organ transplantation, and multiple studies suggest an association between the intensity of immunosuppression and the frequency/severity of herpes zoster episodes [38][39][40][41][42].…”

Accelerated immune senescence and reduced response to vaccination in ovariectomized female rhesus macaques

“…A representative example of Ki67 staining from one animal is shown in Fig. 3a where the frequency of CD4 CM and CD8 CM expressing Ki67 increases on day 7 post-vaccination compared to day 0 (Messaoudi et al 2009). T cells in all four Tcell subsets (CD8 CM, CD8 EM, CD4 CM, and CD4 EM) from intact adult females underwent a robust proliferative burst 7 days after the first immunization and a smaller burst 7 days after the booster dose (35) (Fig.…”