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. Objective: To compare six novel vaccine regimens to induce CD4+ and CD8+ T Cells against SIV epitopes. Recent failures in clinical HIV vaccines have underscored the importance of more thoroughly evaluating basic science of HIV as well as testing new vaccine regimens and vectors. In an effort to overcome the limitations of more traditional vector-based vaccines, our laboratory has developed several novel immunization strategies. These new methods will allow us to directly prime specific T cell responses in a manner that previously has been impossible with other vaccine vectors and regimens. This should allow us to dissect the contributions of specific T cell responses in the control of SIV replication -- for the roles of both subdominant CD8+ T cells and virus-specific CD4+ T cells. In the R21 phase of this grant, we will compare six novel vaccination regimens: peptide-pulsed dendritic cells, peptide-conjugated nanobeads, peptide-pulsed PBMC, SIV peptides fused to a Hepatitis B core antigen (HBcAg) carrier gene, electroporated DNA+IL-12 and Adenovirus5. PROGRESS: We have completed vaccinating animals in groups one and two of the R21 phase. These animals received autologous dendritic cells pulsed with three Mamu-DRbw*606-restricted CD4 epitopes and primed with either autologous PBMC pulsed with the same epitopes or peptide-conjugated nanobeads. Two weeks after the final boosts, no animals made any detectable epitope-specific CD4+ T cell responses as detected by ELISPOT or ICS. The HBcAg vectors were completed by Dr. Deborah Fuller with each of the selected Mamu-A*01-restricted CD8 epitopes inserted into individual vectors. Six Mamu-A*01+ animals, groups three and four, received five doses of the HBcAg vector. After the fifth dose, no animals made any detectable epitope-specific CD8+ T cell response;however, they did respond well to Hepatitis peptide provided by Dr. Fuller indicating that they did receive doses of the vaccine. One month after the final prime, one group received autologous PBMC pulsed with each of the A*01 epitopes, while the other group received the A*01 epitopes conjugated to nanobeads. After boosting these animals, we still saw no detectable epitope-specific CD8+ T cell responses. Additionally, we made DNA and Adenovirus5 vectors containing the three CD4 epitopes and the five CD8 epitopes. We vaccinated animals with these constructs in the hope of eliciting epitope-specific CD4+ and CD8+ T cell responses. Two weeks after the Ad5 boost, we detected high frequency SIV-specific CD4+ T cell responses against all three epitopes in the vaccine. Two of the three animals made responses to all three epitopes, while the third animal made responses to two of the three epitopes. All three animals that received the CD8 epitopes made a high frequency response to one epitope in Env: Env TL9. One animal made an additional Pol LV10-specific CD8+ T cell response. While the epitope-specific CD4 vaccination was successful, none of the tested vaccine regimens elicited several high frequency epitope-specific CD8+ T cell responses. A publication is in preparation.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Primate Research Center Grants (P51)
Project #
5P51RR000167-50
Application #
8358223
Study Section
Special Emphasis Panel (ZRR1-CM-8 (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
$95,337
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Other Domestic Higher Education
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Ellis, Amy; Balgeman, Alexis; Rodgers, Mark et al. (2017) Characterization of T Cells Specific for CFP-10 and ESAT-6 in Mycobacterium tuberculosis-Infected Mauritian Cynomolgus Macaques. Infect Immun 85:
Mattison, Julie A; Colman, Ricki J; Beasley, T Mark et al. (2017) Caloric restriction improves health and survival of rhesus monkeys. Nat Commun 8:14063
Buechler, Connor R; Bailey, Adam L; Lauck, Michael et al. (2017) Genome Sequence of a Novel Kunsagivirus (Picornaviridae: Kunsagivirus) from a Wild Baboon (Papio cynocephalus). Genome Announc 5:
Rodrigues, Michelle A (2017) Female Spider Monkeys (Ateles geoffroyi) Cope with Anthropogenic Disturbance Through Fission-Fusion Dynamics. Int J Primatol 38:838-855
Wu, Hong; Whritenour, Jessica; Sanford, Jonathan C et al. (2017) Identification of MHC Haplotypes Associated with Drug-induced Hypersensitivity Reactions in Cynomolgus Monkeys. Toxicol Pathol 45:127-133
Shackman, A J; Fox, A S; Oler, J A et al. (2017) Heightened extended amygdala metabolism following threat characterizes the early phenotypic risk to develop anxiety-related psychopathology. Mol Psychiatry 22:724-732
Kalin, Ned H (2017) Mechanisms underlying the early risk to develop anxiety and depression: A translational approach. Eur Neuropsychopharmacol 27:543-553
Singaravelu, Janani; Zhao, Lian; Fariss, Robert N et al. (2017) Microglia in the primate macula: specializations in microglial distribution and morphology with retinal position and with aging. Brain Struct Funct 222:2759-2771
Feltovich, Helen (2017) Cervical Evaluation: From Ancient Medicine to Precision Medicine. Obstet Gynecol 130:51-63
Sutton, Matthew S; Burns, Charles M; Weiler, Andrea M et al. (2016) Vaccination with Live Attenuated Simian Immunodeficiency Virus (SIV) Protects from Mucosal, but Not Necessarily Intravenous, Challenge with a Minimally Heterologous SIV. J Virol 90:5541-8

Showing the most recent 10 out of 523 publications