The central importance of virus-specific CD4+ T lymphocytes in containing HIV-1 replication has recently been appreciated. Studies have shown that control of viral replication in vivo is associated with vigorous HIV-1-specific CD4+ T lymphocyte proliferative responses. It will be important to characterize of these lymphocytes in greater depth to determine how they contribute to containing HIV-1 replication. However, our ability to study these lymphocyte populations has been limited by the technologies available to carry out such analyses. By providing a reproducible and precise quantitative assay for CTL responses, the tetramer assay has dramatically increased the level of sophistication that can be brought to bear on the study of antigen-specific CD8+ T lymphoctes. The application of the tetramer technology to the study of CD4+ T lymphocyte responses should similarly increase our ability to evaluate the role of these cells in disease pathogenesis. Pooled peptide-stimulated cytokine production assays will also be useful. In the studies described in the present application, we will develop these technologies for studying Sly- and simian human immunodeficiency virus (SHIV)-specific CD4+ T lymphocytes in rhesus monkeys. Specifically, we will: 1. Perform CD4+ T lymphocyte epitope mapping in SHIV- and SIV-infected rhesus monkeys. 2. Construct and assess of MHC class II/immunoglobulin dimeric and decameric staining reagents. 3. Construct novel MamuDR*W201/peptide tetramers. 4. Apply quantitative technologies to the use of Mamu-DR*W201/peptide tetramers. 5. Adapt cytokine-based assays for detecting SHIV-and SIV-specific CD4+ T lymphocytes. 6. Evaluate CD4+ epitopespecific T lymphocyte responses during primary SHIV-IIIB and SIVmac25l infections. 7. Assess virus epitopespecific CD4+ T cell responses in chronically SIVmac-infected rhesus monkeys. 8. Determine the repertoire of SIVmac epitopes recognized by CD4+ T lymphocytes during structured interruptions of anti-retroviral therapy.
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| Subbramanian, Ramu A; Moriya, Chikaya; Martin, Kristi L et al. (2004) Engineered T-cell receptor tetramers bind MHC-peptide complexes with high affinity. Nat Biotechnol 22:1429-34 |
| Newberg, Michael H; Kuroda, Marcelo J; Charini, William A et al. (2002) A simian immunodeficiency virus nef peptide is a dominant cytotoxic T lymphocyte epitope in Indian-origin rhesus monkeys expressing the common MHC class I allele mamu-A*02. Virology 301:365-73 |
