Attenuation of the Adaptive Immune Response in Rhesus Macaques Infected with Simian Varicella Virus Lacking Open Reading Frame 61

Vaccine and Gene Therapy Institute.
Journal of Virology (Impact Factor: 4.44). 12/2012; 87(4). DOI: 10.1128/JVI.02369-12
Source: PubMed


Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus that causes chickenpox during primary infection and establishes latency in sensory ganglia. Infection of rhesus macaques (RM) with the homologous simian varicella virus (SVV) recapitulates hallmarks of VZV infection. We have shown that an antisense transcript of SVV open reading frame (ORF) 61, a viral transactivator, was detected most frequently in latently infected RMs sensory ganglia. In this study, we compared disease progression, viral replication, immune response and the establishment of latency following intrabronchial infection with a recombinant SVV lacking ORF61 (SVVΔORF61) to wild-type (WT) SVV. Varicella severity, and viral latency within sensory ganglia were comparable in RMs infected with SVVΔORF61 or WT SVV. In contrast, viral loads, B and T cell responses and plasma inflammatory cytokine levels were decreased in RMs infected with SVVΔORF61. To investigate the mechanisms underlying the reduced adaptive immune response, we compared acute SVV gene expression, frequency and proliferation of dendritic cell (DC) subsets, and the expression of innate antiviral genes in bronchoalveolar lavage (BAL) samples. The abundance of SVV transcripts in all kinetic classes was significantly decreased in RMs infected with SVVΔORF61. In addition, we detected a higher frequency and proliferation of plasmacytoid dendritic cells in BAL at 3 days post-infection in RMs infected with SVVΔORF61, which was accompanied a slight increase in type I interferon gene expression. Taken together our data suggest that ORF61 plays an important role in orchestrating viral gene expression in vivo and may interfere with the host antiviral interferon response.

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    • "High levels of pro-inflammatory mediators IFN-γ, IL-6, MCP-1, IP-10 and I-TAC and anti-inflammatory cytokine IL-1Ra were seen at 4–14 dpi in all five monkeys. Our results confirm and extend a recent report of increased levels of IL-6, IFN-γ and IL-1Ra during primary SVV infection in rhesus macaques (Meyer et al. 2013), findings consistent with a strong pulmonary innate immune response to SVV after respiratory exposure. IFN-γ is produced by lymphocytes during primary varicella zoster virus infection (Arvin et al. 1986) and suppresses VZV replication in vitro (Rabalais et al. 1989). "
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