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Simian varicella virus infection of rhesus macaques recapitulates essential features of varicella zoster virus infection in humans.

Messaoudi I, Barron A, Wellish M, Engelmann F, Legasse A, Planer S, Gilden D, Nikolich-Zugich J, Mahalingam R - PLoS Pathog. (2009)

Bottom Line: 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.Intrabronchial inoculation of rhesus macaques with SVV provides a novel model to analyze viral and immunological mechanisms of VZV latency and reactivation.

View Article: PubMed Central - PubMed

Affiliation: Vaccine and Gene Therapy, Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon, United States of America. messaoud@ohsu.edu

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.

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Detection of SVV ORF 63 protein in the cytoplasm of neurons in monkey ganglia latently infected with SVV.Paraformaldehyde-fixed, paraffin-embedded sections (5 µ) of thoracic (th) ganglia from monkey 23986, trigeminal (tg) ganglia from monkey 23942 and thoracic ganglia from monkey 24953 were analyzed by immunohistochemistry using a 1∶800 dilution of rabbit anti-VZV ORF 63 (anti-VZV63), a 1∶1000 dilution of rabbit anti-VZV ORF 61 (anti VZV61) antiserum or normal rabbit serum (NRS). SVV ORF 63 protein was detected in thoracic and trigeminal ganglia of monkeys 23986 and 23942, respectively, and SVV ORF 61 protein was detected in thoracic ganglia of monkey 24953. No SVV antigen was seen using normal rabbit serum. SVV ORF63 protein, but not SVV ORF61 protein was detected in trigeminal ganglia of monkey 23942.
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ppat-1000657-g002: Detection of SVV ORF 63 protein in the cytoplasm of neurons in monkey ganglia latently infected with SVV.Paraformaldehyde-fixed, paraffin-embedded sections (5 µ) of thoracic (th) ganglia from monkey 23986, trigeminal (tg) ganglia from monkey 23942 and thoracic ganglia from monkey 24953 were analyzed by immunohistochemistry using a 1∶800 dilution of rabbit anti-VZV ORF 63 (anti-VZV63), a 1∶1000 dilution of rabbit anti-VZV ORF 61 (anti VZV61) antiserum or normal rabbit serum (NRS). SVV ORF 63 protein was detected in thoracic and trigeminal ganglia of monkeys 23986 and 23942, respectively, and SVV ORF 61 protein was detected in thoracic ganglia of monkey 24953. No SVV antigen was seen using normal rabbit serum. SVV ORF63 protein, but not SVV ORF61 protein was detected in trigeminal ganglia of monkey 23942.

Mentions: VZV ORF 63 protein is present in the cytoplasm of neurons in latently infected human ganglia [29],[30]. To determine whether SVV ORF 63 protein is comparably localized, sections of formalin-fixed ganglia from the side of the neuraxis opposite to the one used for nucleic acid analysis were studied using immunohistochemistry for SVV ORF 63 protein as well as for SVV ORF 61 protein in light of the considerable abundance of SVV ORF 61 transcripts. VZV ORF 63- or 61-specific rabbit polyclonal antisera, which reacted with SVV-infected cells in culture (Figure S1A, C) but not with uninfected Vero cells (Figure S1B, D), were used in these studies. We detected SVV ORF 63 protein exclusively in the cytoplasm of ganglionic neurons in all animals (Figure 2A and B). SVV ORF 61 protein was detected in one ganglion from two monkeys (Table 5) in both the nucleus and cytoplasm (Figure 2). Analysis of adjacent sections of trigeminal ganglia from monkey 23942 revealed the presence of SVV ORF 63 but not 61 (Figure 2). Table 5 summarizes results from ganglia of all 4 monkeys and shows that like VZV ORF63, SVV ORF63 is consistently detected in the cytoplasm of neurons in latently infected ganglia. Overall, these data suggest that SVV infection in rhesus macaques recapitulates key features of VZV latency.


Simian varicella virus infection of rhesus macaques recapitulates essential features of varicella zoster virus infection in humans.

Messaoudi I, Barron A, Wellish M, Engelmann F, Legasse A, Planer S, Gilden D, Nikolich-Zugich J, Mahalingam R - PLoS Pathog. (2009)

Detection of SVV ORF 63 protein in the cytoplasm of neurons in monkey ganglia latently infected with SVV.Paraformaldehyde-fixed, paraffin-embedded sections (5 µ) of thoracic (th) ganglia from monkey 23986, trigeminal (tg) ganglia from monkey 23942 and thoracic ganglia from monkey 24953 were analyzed by immunohistochemistry using a 1∶800 dilution of rabbit anti-VZV ORF 63 (anti-VZV63), a 1∶1000 dilution of rabbit anti-VZV ORF 61 (anti VZV61) antiserum or normal rabbit serum (NRS). SVV ORF 63 protein was detected in thoracic and trigeminal ganglia of monkeys 23986 and 23942, respectively, and SVV ORF 61 protein was detected in thoracic ganglia of monkey 24953. No SVV antigen was seen using normal rabbit serum. SVV ORF63 protein, but not SVV ORF61 protein was detected in trigeminal ganglia of monkey 23942.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2770849&req=5

ppat-1000657-g002: Detection of SVV ORF 63 protein in the cytoplasm of neurons in monkey ganglia latently infected with SVV.Paraformaldehyde-fixed, paraffin-embedded sections (5 µ) of thoracic (th) ganglia from monkey 23986, trigeminal (tg) ganglia from monkey 23942 and thoracic ganglia from monkey 24953 were analyzed by immunohistochemistry using a 1∶800 dilution of rabbit anti-VZV ORF 63 (anti-VZV63), a 1∶1000 dilution of rabbit anti-VZV ORF 61 (anti VZV61) antiserum or normal rabbit serum (NRS). SVV ORF 63 protein was detected in thoracic and trigeminal ganglia of monkeys 23986 and 23942, respectively, and SVV ORF 61 protein was detected in thoracic ganglia of monkey 24953. No SVV antigen was seen using normal rabbit serum. SVV ORF63 protein, but not SVV ORF61 protein was detected in trigeminal ganglia of monkey 23942.
Mentions: VZV ORF 63 protein is present in the cytoplasm of neurons in latently infected human ganglia [29],[30]. To determine whether SVV ORF 63 protein is comparably localized, sections of formalin-fixed ganglia from the side of the neuraxis opposite to the one used for nucleic acid analysis were studied using immunohistochemistry for SVV ORF 63 protein as well as for SVV ORF 61 protein in light of the considerable abundance of SVV ORF 61 transcripts. VZV ORF 63- or 61-specific rabbit polyclonal antisera, which reacted with SVV-infected cells in culture (Figure S1A, C) but not with uninfected Vero cells (Figure S1B, D), were used in these studies. We detected SVV ORF 63 protein exclusively in the cytoplasm of ganglionic neurons in all animals (Figure 2A and B). SVV ORF 61 protein was detected in one ganglion from two monkeys (Table 5) in both the nucleus and cytoplasm (Figure 2). Analysis of adjacent sections of trigeminal ganglia from monkey 23942 revealed the presence of SVV ORF 63 but not 61 (Figure 2). Table 5 summarizes results from ganglia of all 4 monkeys and shows that like VZV ORF63, SVV ORF63 is consistently detected in the cytoplasm of neurons in latently infected ganglia. Overall, these data suggest that SVV infection in rhesus macaques recapitulates key features of VZV latency.

Bottom Line: 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.Intrabronchial inoculation of rhesus macaques with SVV provides a novel model to analyze viral and immunological mechanisms of VZV latency and reactivation.

View Article: PubMed Central - PubMed

Affiliation: Vaccine and Gene Therapy, Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon, United States of America. messaoud@ohsu.edu

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.

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Related in: MedlinePlus