Simian Varicella Virus Is Present in Macrophages, Dendritic Cells, and T Cells in Lymph Nodes of Rhesus Macaques after Experimental Reactivation

Abstract

Like varicella-zoster virus (VZV), simian varicella virus (SVV) reactivates to produce zoster. In the present study, 5 rhesus macaques were inoculated intrabronchially with SVV, and 5 months later, 4 monkeys were immunosuppressed; 1 monkey was not immunosuppressed but was subjected to the stress of transportation. In 4 monkeys, a zoster rash developed 7 to 12 weeks after immunosuppression, and a rash also developed in the monkey that was not immunosuppressed. Analysis at 24 to 48 h after zoster revealed SVV antigen in the lung alveolar wall, in ganglionic neurons and nonneuronal cells, and in skin and in lymph nodes. In skin, SVV was found primarily in sweat glands. In lymph nodes, the SVV antigen colocalized mostly with macrophages, dendritic cells, and, to a lesser extent, T cells. The presence of SVV in lymph nodes, as verified by quantitative PCR detection of SVV DNA, might reflect the sequestration of virus by macrophages and dendritic cells in lymph nodes or the presentation of viral antigens to T cells to initiate an immune response against SVV, or both. IMPORTANCEVZV causes varicella (chickenpox), becomes latent in ganglia, and reactivates to produce zoster and multiple other serious neurological disorders. SVV in nonhuman primates has proved to be a useful model in which the pathogenesis of the virus parallels the pathogenesis of VZV in humans. Here, we show that SVV antigens are present in sweat glands in skin and in macrophages and dendritic cells in lymph nodes after SVV reactivation in monkeys, raising the possibility that macrophages and dendritic cells in lymph nodes serve as antigen-presenting cells to activate T cell responses against SVV after reactivation. P rimary varicella-zoster virus (VZV) infection produces chickenpox (varicella), after which the virus becomes latent in ganglionic neurons along the entire neuraxis. As VZV-specific T cell immunity declines with advancing age, VZV reactivates to produce zoster, which may be complicated by multiple neurological and ocular disorders. Simian varicella virus (SVV) infection of nonhuman primates has served as a good model with which to study the pathogenesis of VZV because of the pathological, immunological, and virological similarities of SVV to VZV (1, 2). VZV reactivation is increased in patients receiving chemotherapy or after X-irradiation (3); similarly, SVV reactivates in latently infected African green monkeys (AGM) and cynomolgus monkeys (CM) after immunosuppression and environmental stress (4). In rhesus macaques, intrabronchial inoculation with SVV produces varicella, followed by the establishment of latency (5) and virus reactivation after X-irradiation (6, 7). At the time of SVV reactivation in CM, expression of CXCL10 (a chemokine which recruits activated T cells and NK cells) correlates with transient T cell infiltration in ganglia (8). In the study described here, we determined if a combination of irradiation and treatment with prednisone and tacrolimus induces reactivation of SVV in latently infected rhesus macaques to s...

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

“…Isotype control did not reveal any staining (data not shown). Consistent with our earlier observations (30), SVV antigens colocalized more often in macrophages than in any other cells, and no SVV antigens were detected in lymph nodes from latently infected or SVV-seronegative monkeys. SVV antigen was found in multiple lymph nodes in all monkeys, only some of which were associated with areas of rash.…”

“…4E). Although SVV antigens were detected in the lungs from all monkeys (data not shown), similar to our earlier observations (30), the number of antigen-positive cells in lungs was substantially less than in lymph nodes. SVV glycoproteins gH and gL were detected mostly in the cytoplasm of neurons and, less frequently, in nonneuronal cells in thoracic ganglia from monkey JF07 (Fig.…”

“…SVV antigens were detected in macrophages and dendritic cells in lymph nodes. The presence of SVV in lymph nodes, as verified by quantitative PCR detection of SVV DNA, may reflect SVV infection of these cells in lymph nodes or the presentation of viral antigens to T cells to induce an immune response against SVV or both (30). Recently, Arnold et al (31) demonstrated subclinical SVV reactivation in rhesus macaques thymectomized and depleted in CD4 and CD8 T cells.…”

Robust gene expression changes in the ganglia following subclinical reactivation in rhesus macaques infected with simian varicella virus

“…We previously showed that this model recapitulates the essential features of VZV infection in humans including varicella and establishment of latency in sensory ganglia (Messaoudi et al , 2009). Moreover, as described for VZV, SVV reactivates under conditions of immune suppression (Mahalingam et al , 2010; Mahalingam et al , 2007b; Ouwendijk et al , 2013; Traina-Dorge et al , 2015). To investigate the role that T cell senescence plays in SVV reactivation, rhesus macaques latently infected with SVV were first thymectomized and then depleted of either CD4 or CD8 T cells.…”

Alpha-synuclein supports interferon stimulated gene expression in neurons

“…Next, we evaluated histology of dorsal root ganglia from rhesus macaques after simian varicella virus (SVV), a DNA virus related to human varicella zoster virus, reactivation as previously described. (19) We found increased levels of pS129 asyn in 15 dorsal root ganglion from SVV-infected rhesus macaques compared to seronegative control rhesus macaques ( Fig. 4D-F).…”