16 different NIH institutes invest more than $200,000,000 in projects studying T cell responses to simian immunodeficiency virus (SIV), tuberculosis, and influenza. The specificity of cellular CD8+ and CD4+ T cell responses are determined by an individual's repertoire of major histocompatibility complex (MHC) class I and class II alleles, respectively. The apparent complexity of macaque MHC genetics has discouraged investigators from fine-mapping epitope- specific T cell responses. Consequently, only a small number of SIV-specific T cell responses have been characterized in depth, while nearly nothing is known about epitope-specific T cell responses against influenza and BCG (the current vaccine for tuberculosis) in macaques. This constrains investigators interested in monitoring or evaluating T cell responses. Tellingly, there have been shortages of animals possessing the few MHC alleles for which SIV-specific T cell responses and reagents (e.g., MHC:peptide tetramers) are available. Our laboratory recently discovered that MHC allele sharing in Indian rhesus macaques is more common than previously realized. More than 99% of Indian rhesus macaques possess at least one of 16 common MHC class I alleles, while 94% have at least one of 9 common MHC class II -DRB alleles. In this project, we will: 1) Sequentially infect Indian rhesus macaques possessing these 25 common MHC alleles with influenza, BCG, and SIV. T cell responses against all three pathogens will be mapped. 2) Fine-map the epitope specificity and determine the MHC restriction of these CD8+ and CD4+ responses. 3) Produce and distribute MHC:peptide tetramers for responses restricted by the 25 common MHC alleles. We will make new tetramers to measure both CD8+ and CD4+ T cell responses against SIV, influenza, and BCG. The T cell epitopes and MHC:peptide tetramers will be a valuable resource for investigators studying cellular immunity to major infectious diseases. Our team's expertise studying cellular immunity and pathogenesis to SIV, influenza, and BCG in macaque monkeys and our experience with MHC:peptide tetramer production and validation uniquely qualifies us to undertake this ambitious project.

Public Health Relevance

T cells are important components of the immune response to HIV, influenza, and BCG (the current tuberculosis vaccine). Knowledge of the targets recognized by CD8+ T and CD4+ cells is essential to study these responses; however, few targets have been identified in Indian rhesus macaques (InRh). We will define T cell responses against these three pathogens that will be applicable to nearly all InRh.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Resource-Related Research Projects (R24)
Project #
5R24OD017850-04
Application #
9281065
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hild, Sheri Ann
Project Start
2014-09-01
Project End
2019-05-31
Budget Start
2017-06-01
Budget End
2019-05-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Pathology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Aliota, Matthew T; Dudley, Dawn M; Newman, Christina M et al. (2018) Molecularly barcoded Zika virus libraries to probe in vivo evolutionary dynamics. PLoS Pathog 14:e1006964
Wu, Helen L; Wiseman, Roger W; Hughes, Colette M et al. (2018) The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques. J Immunol 200:49-60
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:
Bailey, Adam L; Buechler, Connor R; Matson, Daniel R et al. (2017) Pegivirus avoids immune recognition but does not attenuate acute-phase disease in a macaque model of HIV infection. PLoS Pathog 13:e1006692
Ericsen, Adam J; Lauck, Michael; Mohns, Mariel S et al. (2016) Microbial Translocation and Inflammation Occur in Hyperacute Immunodeficiency Virus Infection and Compromise Host Control of Virus Replication. PLoS Pathog 12:e1006048
Ayala, Victor I; Trivett, Matthew T; Coren, Lori V et al. (2016) A novel SIV gag-specific CD4(+)T-cell clone suppresses SIVmac239 replication in CD4(+)T cells revealing the interplay between antiviral effector cells and their infected targets. Virology 493:100-12
Gellerup, Dane D; Balgeman, Alexis J; Nelson, Chase W et al. (2016) Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection. J Virol 90:545-52
Dudley, Dawn M; Aliota, Matthew T; Mohr, Emma L et al. (2016) A rhesus macaque model of Asian-lineage Zika virus infection. Nat Commun 7:12204
Mohns, Mariel S; Greene, Justin M; Cain, Brian T et al. (2015) Expansion of Simian Immunodeficiency Virus (SIV)-Specific CD8 T Cell Lines from SIV-Naive Mauritian Cynomolgus Macaques for Adoptive Transfer. J Virol 89:9748-57