This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cytomegalovirus (CMV) infection in an immunocompetent individual infrequently causes clinical signs of infection. In contrast, CMV infection in those without a functional immune system is a significant cause of morbidity and mortality. This includes CMV infections in those co infected with HIV. Therefore, CMV vaccine strategies developed will have direct clinical relevance to protecting those most at risk for CMV disease, including HIV AIDS patients. Since human cytomegalovirus (HCMV) was first recognized as a threat to the developing fetus, there have been repeated calls for a vaccine that could protect from the damaging effects of HCMV infection in those at risk for HCMV disease. The long quest for a HCMV vaccine that could prevent congenital infection and fetal sequelae, as well as end- organ disease in immune compromised individuals, remains unfulfilled. The primary objective measure for evaluating the efficiency of any vaccine is whether protective levels of immunity are generated and sustained in the vaccinees. An important issue for HCMV is the definition of what constitutes protective immunity. Using a stringent threshold, an immune response can be considered protective only if the vaccinees are absolutely protected from infection following repeated exposure to virus. Alternatively, a vaccine could still be considered protective if the course of challenge virus infection was so dramatically altered that the potential for transmission (horizontal and vertical) and pathogenesis of challenge virus was essentially eliminated. The difference between the two involves the level of virus replication at the primary site of challenge and the extent of dissemination beyond. The former definition requires the generation and maintenance of sterilizing immunity with no spread of the virus. The latter does not, but it does require that the immune system maintain a lifelong restriction on replication of a virus with a complex natural history of persistence in immune competent hosts. The hypothesis is presented that immunization against CMV can generate protective immune responses, although the degree of protection (sterilizing versus limited dissemination) will be dependent on both the titer of challenge virus and the frequency of exposure. According to this hypothesis, immunization can protect completely against infrequent exposure to a low titer CMV challenge. Protection will become more variable as the titer and/or the frequency of exposure to challenge virus increases. Vaccination should shift the virus-host balance decidedly in favor of the host such that both reactivation and shedding are significantly diminished. The hypothesis will be tested in the rhesus macaque model of HCMV infection through the following Aims. (I) Genetic immunization of seronegative macaques with plasmid expression vectors for RhCMV gB, pp65, and IE1, followed by immunization with formalin-inactivated virus. (II) Subcutaneous challenge of vaccinees and controls by experimental inoculation with either high or low titers of RhCMV. (III) Immunization of macaques followed by challenge of vaccinees and controls by natural routes with natural titers of RhCMV by co-housing vaccinees with seropositive, virus-excreting macaques. (IV) Alterations of RhCMV gene expression patterns to induce novel protective immune responses. A CMV vaccine can be considered protective if it results in a dead-end infection. This proposal will stringently test whether a combination of genetic immunization and formalin-inactivated virus can effectively eliminate horizontal spread of RhCMV following either experimental or natural infection.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000169-50
Application #
8357278
Study Section
Special Emphasis Panel (ZRR1-CM-5 (01))
Project Start
2011-05-01
Project End
2012-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
50
Fiscal Year
2011
Total Cost
$191,444
Indirect Cost
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Midic, Uros; VandeVoort, Catherine A; Latham, Keith E (2018) Determination of single embryo sex in Macaca mulatta and Mus musculus RNA-Seq transcriptome profiles. Physiol Genomics 50:628-635
Almodovar, Sharilyn; Swanson, Jessica; Giavedoni, Luis D et al. (2018) Lung Vascular Remodeling, Cardiac Hypertrophy, and Inflammatory Cytokines in SHIVnef-Infected Macaques. Viral Immunol 31:206-222
Ciupe, Stanca M; Miller, Christopher J; Forde, Jonathan E (2018) A Bistable Switch in Virus Dynamics Can Explain the Differences in Disease Outcome Following SIV Infections in Rhesus Macaques. Front Microbiol 9:1216
Comrie, Alison E; Gray, Daniel T; Smith, Anne C et al. (2018) Different macaque models of cognitive aging exhibit task-dependent behavioral disparities. Behav Brain Res 344:110-119
Day, George Q; Ng, Jillian; Oldt, Robert F et al. (2018) DNA-based Determination of Ancestry in Cynomolgus Macaques (Macaca fascicularis). J Am Assoc Lab Anim Sci 57:432-442
Carroll, Timothy D; Jegaskanda, Sinthujan; Matzinger, Shannon R et al. (2018) A Lipid/DNA Adjuvant-Inactivated Influenza Virus Vaccine Protects Rhesus Macaques From Uncontrolled Virus Replication After Heterosubtypic Influenza A Virus Challenge. J Infect Dis 218:856-867
Feng, Jun-Feng; Liu, Jing; Zhang, Lei et al. (2017) Electrical Guidance of Human Stem Cells in the Rat Brain. Stem Cell Reports 9:177-189
Han, Pengcheng; Nielsen, Megan; Song, Melissa et al. (2017) The Impact of Aging on Brain Pituitary Adenylate Cyclase Activating Polypeptide, Pathology and Cognition in Mice and Rhesus Macaques. Front Aging Neurosci 9:180
Pittet, Florent; Johnson, Crystal; Hinde, Katie (2017) Age at reproductive debut: Developmental predictors and consequences for lactation, infant mass, and subsequent reproduction in rhesus macaques (Macaca mulatta). Am J Phys Anthropol 164:457-476
Kyle, Colin T; Stokes, Jared; Bennett, Jeffrey et al. (2017) Cytoarchitectonically-driven MRI atlas of nonhuman primate hippocampus: Preservation of subfield volumes in aging. Hippocampus :

Showing the most recent 10 out of 408 publications