Reactivation of latent varicella zoster virus (VZV) leads to herpes zoster (HZ, also known as shingles), a disease that causes major morbidity and occasionally mortality in older individuals. The incidence of HZ increases from 3.3 per 1000 person-years at age 40-49 to 7.7 at age 60-69. Advanced age is the primary risk factor not only for developing HZ, but also complications such as post herpetic neuralgia, vasculopathies and zoster opthalmicus. Current estimates predict that by 2020 more than 70 million Americans will be over the age of 65 therefore, the incidence of HZ and associated complications will certainly increase. Furthermore, the currently approved vaccine against HZ reduces the incidence of shingles by only 51%. Thus, a significant portion of the vaccine recipients still remains susceptible to VZV reactivation. A major obstacle in developing better treatments and vaccines for HZ is that models utilizing VZV infection of laboratory animals do not produce signs of in clinical disease that occur in humans. Consequently, our understanding of the immune correlates of protection against VZV infection and reactivation remains very limited due to lack of a suitable animal model to study host-pathogen interactions in vivo. We have developed a nonhuman primate model wherein young rhesus macaques infected with a primate homologue of human VZV, simian varicella virus (SVV) display the hallmarks of VZV infection in humans;i.e., the appearance of generalized varicella rash, the development of cellular and humeral immunity, and the establishment of latency with limited transcriptional activity in sensory ganglia. In contrast to young rhesus macaques, aged animals infected with SVV remain persistently viremic. In aged monkeys, persistent lytic replication occurred despite the development of an IgG antibody response that was comparable to that generated by young animals. On the other hand, SVV-specific T cell responses in aged animals were significantly delayed compared to those generated by young animals. These data strongly suggest that, as described for VZV, defects in T cell responses in aged animals result in poor immunological control of SVV replication and dissemination. Further evidence for this hypothesis was obtained from young rhesus macaques depleted of either CD4 or CD8 T cells and then infected with SVV. In CD8 T cell-depleted animals, SVV antigen was persistently detected in the lungs despite presence of a comparable IgG response to non-depleted controls. In CD4 T cell-depleted animals, the IgG response was significantly delayed and reduced. However, although IgG titers reached comparable levels as the controls in one CD4 T cell-depleted animal, it remained persistently viremic nevertheless. These data strongly suggest that, as described for VZV, the development and maintenance of a robust T cell response is critical to the control of SVV infection. Therefore, SVV infection of young and aged rhesus macaques provides a unique opportunity to: (1) identify age-related differences in the SVV-specific T cell responses and (2) determine how these differences in immune responses affect the aged animal's ability to control SVV replication and to maintain latency. These studies will improve our understanding of immunological control of latent VZV as well as other latent pathogens that pose significant health issues for the elderly.

Public Health Relevance

Herpes zoster (HZ), or shingles, is caused by reactivation of latent varicella zoster virus (VZV) and causes significant morbidity and sometimes mortality in the elderly. Although it is generally believed that decreased T cell immunity is the underlying cause of HZ, the specific defects remain poorly understood. In this application, we will employ a novel and robust nonhuman primate model of VZV infection to improve our understanding of the immune control of VZV in the aged, a prerequisite for designing better vaccines and treatment to prevent HZ and other latent pathogens in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG037042-03
Application #
8235846
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Fuldner, Rebecca A
Project Start
2010-04-01
Project End
2012-12-31
Budget Start
2012-04-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$307,683
Indirect Cost
$110,073
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Haberthur, Kristen; Meyer, Christine; Arnold, Nicole et al. (2014) Intrabronchial infection of rhesus macaques with simian varicella virus results in a robust immune response in the lungs. J Virol 88:12777-92
Haberthur, Kristen; Kraft, Aubrey; Arnold, Nicole et al. (2013) Genome-wide analysis of T cell responses during acute and latent simian varicella virus infections in rhesus macaques. J Virol 87:11751-61
Meyer, Christine; Dewane, Jesse; Kerns, Amelia et al. (2013) Age and immune status of rhesus macaques impact simian varicella virus gene expression in sensory ganglia. J Virol 87:8294-306
Meyer, Christine; Dewane, Jesse; Haberthur, Kristen et al. (2013) Bacterial artificial chromosome derived simian varicella virus is pathogenic in vivo. Virol J 10:278
Meyer, Christine; Kerns, Amelia; Haberthur, Kristen et al. (2013) Attenuation of the adaptive immune response in rhesus macaques infected with simian varicella virus lacking open reading frame 61. J Virol 87:2151-63
Verweij, Marieke C; Lipinska, Andrea D; Koppers-Lalic, Danijela et al. (2011) The capacity of UL49.5 proteins to inhibit TAP is widely distributed among members of the genus Varicellovirus. J Virol 85:2351-63
Kinchington, Paul R; Goins, William F (2011) Varicella zoster virus-induced pain and post-herpetic neuralgia in the human host and in rodent animal models. J Neurovirol 17:590-9
Meyer, Christine; Kerns, Amelia; Barron, Alex et al. (2011) Simian varicella virus gene expression during acute and latent infection of rhesus macaques. J Neurovirol 17:600-12
Haberthur, Kristen; Engelmann, Flora; Park, Byng et al. (2011) CD4 T cell immunity is critical for the control of simian varicella virus infection in a nonhuman primate model of VZV infection. PLoS Pathog 7:e1002367
Haberthur, Kristen; Engelman, Flora; Barron, Alex et al. (2010) Immune senescence in aged nonhuman primates. Exp Gerontol :

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