Age and Immune Status of Rhesus Macaques Impact Simian Varicella Virus Gene Expression in Sensory Ganglia

Abstract

S imian varicella virus (SVV) and varicella-zoster virus (VZV)are neurotropic alphaherpesviruses that establish latency within the sensory ganglia during primary infection. Viral latency is generally characterized by a quiescent state with limited gene expression; for example, during herpes simplex virus (HSV) latency, only the latency-associated transcripts (LATs) are abundantly expressed (1). However, VZV latency can be associated with the transcription of multiple genes, including open reading frames (ORFs) 4, 11, 18, 21, 29, 40, 41, 43, 57, 62, 63, 66, and 68 (2-9). We recently examined the SVV latent transcriptome from juvenile rhesus macaques (RMs) and found that SVV latency is characterized by a restricted gene expression profile (10). SVV ORF 61 was the most prevalent transcript detected during latent infection, present in at least one sensory ganglion in all RMs tested and in 10 of 16 sensory ganglia total. We also detected SVV ORFs A, B, 4, 10, 55, 63, 64, 65, 66, 67, and 68, although less frequently, in 1 to 4 of 16 latently infected sensory ganglia from juvenile RMs.Several clinical observations highlight the importance of cellmediated immune responses in controlling VZV infection and reactivation. Specifically, a lack of immunoglobulin production due to agammaglobulinemia does not complicate the outcome of varicella in children (11,12). In contrast, T cell deficiencies, including congenital deficiencies or those induced by HIV infection or immune suppression, lead to severe and disseminated varicella (13-17). Similarly, a higher incidence of herpes zoster (HZ) in aged patients is associated with diminished T cell proliferation to VZV antigens in vitro, while antibody titers remain stable (18). Moreover, HIV patients are more susceptible to HZ when their absolute numbers of CD4 T cells decline to less than 500 cells per microliter (19)(20)(21). Finally, the frequency of VZV reactivation is related to the intensity of immune suppression, with higher incidence in patients receiving combined therapy than in patients receiving chemotherapy or radiotherapy alone (22).We have recently shown that the resolution of acute SVV infection is also dependent on cellular immunity. Specifically, loss of CD4 T cells during acute SVV infection in juvenile RMs resulted in higher peak viral loads, prolonged viremia, and disseminated varicella compared to these parameters in controls (23). CD8-depleted RMs had slightly higher viral loads and more prolonged varicella rash than controls. Lastly, CD20 depletion did not alter the severity of varicella or the kinetics and magnitude of the T cell response. Our data indicate that CD4 T cell immunity is critical in controlling acute SVV infection in RMs and are in agreement with clinical observations during acute VZV infection.To improve HZ-associated morbidity, it is critical to understand the virological and immunological parameters that control latency and reactivation. In the present study, we extend our previous reports (10, 23) and investigate the impact of T cell and B c...

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

“…Furthermore, rapid recovery of CD4 T cells, but not CD8 T cells, after stem cell transplants is associated with reduced rates of cytomegalovirus reactivation (Drylewicz et al , 2016). Previous studies from our lab have also shown a greater role for CD4 T cells in the resolution of acute SVV infection where CD4 depleted animals had higher viral loads, prolonged disease and are unable to establish latency in the ganglia (Haberthur et al , 2011; Meyer et al , 2013). On the other hand, CD8+ cells in the trigeminal ganglia play a critical role in the prevention of HSV-1 reactivation in mice (St Leger and Hendricks, 2011), which indicates that immunological control of reactivation may differ between these two closely related viruses.…”

Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

“…Interestingly, we did not detect alpha/beta interferon transcripts. This may be due to the small number of infected cells and the ability of SVV to suppress interferon expression within those infected cells (143,144), which could have diluted the strength of the IFN signal, especially since we were using total ganglion RNA. IFN-stimulated genes could potentially be upregulated within infiltrating innate immune cells.…”

Bacterial artificial chromosome derived simian varicella virus is pathogenic in vivo

“…Specifically, we identified a point mutation at nucleotide 41990 from G to A within ORF22, producing an amino acid change from valine to isoleucine ( Figure 1B) and a transition of nucleotide 106546 from T to C producing a silent mutation within ORF62/71 ( Figure 1C). The nucleotide change in ORF62/71 was also previously shown in the sequencing of an ORF61 deletion virus that was generated from the same parental SVV cosmid system [11][12][13]. SVV ORF22 is a putative tegument protein based on the function of herpes simplex virus type-1 (HSV-1) UL36 homolog.…”