We will determine if HLA analogy extends to cellular reactivity by testing cells from AIDS- infected Chinese rhesus macaques expressing specific alleles of interest. We will also identify MHC alleles that are common in a set of infected animals and characterize them to identify SIV-specific epitopes. We propose to expand and continue the work we performed in our previous AREA grant. In the original grant, we characterized rhesus macaques based on the definition of MHC-peptide binding motifs, data from in vitro MHC-peptide binding assays, and have identified sets of analogous MHC molecules in humans and rhesus macaques. Analogous MHC molecules are defined as MHC molecules associated with a high degree of interspecies cross-reactivity (largely overlapping peptide binding repertoires). We now propose to advance these analyses using new technology consisting of next generation sequencing, to identify MHC molecules in a set of SIV-infected Chinese rhesus macaques. We will determine if HLA analogy extends to cellular reactivity by testing cells from SIV- infected Chinese rhesus macaques expressing specific alleles of interest. Furthermore, we will identify MHC alleles that are common in these infected animals and characterize them to identify SIV- specific epitopes. Our goal is also to understand HLA analogy from a functional perspective as well as identify any new commonly expressed MHC class I alleles. Accordingly, we propose the following specific aims: 1) To identify the complete set of MHC class I alleles in a set of SIVmac239- infected Chinese rhesus macaques using next generation sequencing. 2) To characterize MHC:peptide binding motifs and associated functional immune responses specific in Chinese rhesus macaques. Fifty-six Chinese rhesus macaques are being studied as part of a vaccine study at Washington National Primate Center. We already have preliminary MHC data on a subset of these animals as part of our previous AREA grant. These studies were performed using traditional Sanger sequencing methods. We will now expand the MHC typing of these efforts using next generation sequencing on the [MiSeq platform]. Upon MHC identification of these 56 animals, we will perform additional studies to characterize cellular immune responses. We will receive PBMC which we will use to analyze immune responses. From these data, we will be able to determine cellular reactivity in the context of analogous MHC alleles in Chinese rhesus macaque to HLA alleles and whether there are additional high frequency alleles.

Public Health Relevance

We propose to study a group of non-human primates, rhesus macaques, which have been infected with Simian Immunodeficiency Virus (SIV). These animals represent a unique model of AIDS infection. We propose to characterize immune markers in these animals which are analogous to immune responses in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
2R15AI064175-03A1
Application #
8541665
Study Section
AIDS Molecular and Cellular Biology Study Section (AMCB)
Program Officer
Li, Yen
Project Start
2005-05-15
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2016-01-31
Support Year
3
Fiscal Year
2013
Total Cost
$370,000
Indirect Cost
$120,000
Name
California State University San Marcos
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
176262681
City
San Marcos
State
CA
Country
United States
Zip Code
92078
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Mothé, Bianca R; Southwood, Scott; Sidney, John et al. (2013) Peptide-binding motifs associated with MHC molecules common in Chinese rhesus macaques are analogous to those of human HLA supertypes and include HLA-B27-like alleles. Immunogenetics 65:371-86
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Wambua, Daniel; Henderson, Ryan; Solomon, Christopher et al. (2011) SIV-infected Chinese-origin rhesus macaques express specific MHC class I alleles in either elite controllers or normal progressors. J Med Primatol 40:244-7
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