This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To work on developing a vaccine for HIV, we will identify additional epitopes for cytotoxic and helper T cells and use this information to develop unique reagents for following immune responses. HLA-B27- and -B57-positive HIV-infected humans have long been associated with control of HIV replication, implying that CD8+ T cell responses contribute to control of viral replication. In a similar fashion, fifty percent of Mamu-B*08-positive Indian rhesus macaques control SIVmac239 replication and become elite controllers with chronic phase viremia below 1,000 vRNA copies/ml. Therefore, it is of continuing interest to map epitopes presented by successful vaccinees, as well as the alleles that present them, as a means to more fully understand the immune response to SIV and give SIV researchers more tools and target for vaccine development. In 2008-2009 we defined a motif for Mamu-B*22, which has a frequency of 29%, a fairly high frequency allele. An algorithm has been developed to incorporate this new binding site, predicted peptides have been defined and ordered, and binding studies are underway to determine the peptides which bind with highest affinity. In early 2010, we will test these peptides in SIV infected animals to determine which are actually presented to T cells. All of the cell lines needed for these studies are now in place, and a list of infected animals with this genotype has been developed. We have also defined motifs for Mamu-B*48 (frequency 10%), Mamu-B*52 (frequency 7%) and B*29. We have epitopes defined for Mamu-A*07, and have already published a study featuring this allele. In 2010, we will define motifs for Mamu-B*12, -B*30, -B*47, -B*64 and ?A*06. In 2009 and 2010, we have started mapping epitopes and alleles present in the successful vaccinees from our study published in June 2009. In this study, 6 of 8 vaccinees continue to control viremia below the level of detection. Finally, we are now starting the process of motif determination for MHC class II alleles. We have defined over 30 SIV-defined MHC class II allele and peptide pairs by looking at CD4+ T cell responses present in elite controllers and successful vaccinees. This study also uses resources from the MHC typing facility and Immunology and Virology Services Unit, Elispot and flow cytometry instruments. PUBLICATIONS: Wilson NA, Keele BF, Reed JS, Piaskowski SM, MacNair CE, Bett AJ, Liang X, Wang F, Thoryk E, Heidecker GJ, Citron MP, Huang L, Lin J, Vitelli S, Ahn CD, Kaizu M, Maness NJ, Reynolds MR, Friedrich TC, Loffredo JT, Rakasz EG, Erickson S, Allison DB, Piatak M Jr, Lifson JD, Shiver JW, Casimiro DR, Shaw GM, Hahn BH, Watkins DI. Vaccine-induced cellular responses control simian immunodeficiency virus replication after heterologous challenge. J Virol. 2009 Jul;83(13):6508-21. Epub 2009 Apr 29. PMID: 19403685 Loffredo JT, Sidney J, Bean AT, Beal DR, Bardet W, Wahl A, Hawkins OE, Piaskowski S, Wilson NA, Hildebrand WH, Watkins DI, Sette A. Two MHC class I molecules associated with elite control of immunodeficiency virus replication, Mamu-B*08 and HLA-B*2705, bind peptides with sequence similarity. J Immunol. 2009 Jun 15;182(12):7763-75. PMID: 19494300 Sacha JB, Giraldo-Vela JP, Buechler MB, Martins MA, Maness NJ, Chung C, Wallace LT, Le?n EJ, Friedrich TC, Wilson NA, Hiraoka A, Watkins DI. Gag- and Nef-specific CD4+ T cells recognize and inhibit SIV replication in infected macrophages early after infection. Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9791-6. Epub 2009 May 28. PMID: 19478057
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