MHC-BOUND, SIV-DERIVED, CTL AND HTL EPITOPES

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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 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. PROGRESS: 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, 50 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. While we had hoped to be testing peptides for Mamu-B*22 in vaccinated and infected animals of that genotype, there has been a delay in the affinity determination studies due to technical issues with the Mamu-B*22 monomers produced by our collaborators. Once Dr. Sette's group has completed these determinations, we will continue to map these peptides in 2011. 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 2011, we will continue to define motifs for Mamu-B*12, -B*30, -B*47, -B*64 and A*06. In 2009 and 2010, we started mapping epitopes and alleles present in the successful vaccinees from our study published in June 2009. In this study, six of eight vaccinees continue to control viremia below the level of detection. In addition, in our new vaccination studies, we have deliberately included Mamu-A*07 and Mamu-B*22 positive animals in order to facilitate the development of cell lines and mapping of these epitopes. We have 13 potential epitopes of which five have been confirmed and some of these were also induced during our vaccination. The animals in the new vaccination/challenge study will be challenged starting in February, so at that time we will be able to follow these vaccine-induced responses and determine to what extent they are able to reduce viremia in these animals. We are preparing a manuscript to describe these responses. 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. We have genotyped the animals in the new vaccine/challenge study and have observed development of these MHC class II-restricted responses during the vaccine phase. We have developed one MHC class II tetramer, but only have limited amounts for use during this study. This study also uses resources from the MHC typing facility and Virology & Immunology Services Unit, Elispot and flow cytometry instruments. PUBLICATIONS: Giraldo-Vela JP, Bean AT, Rudersdorf R, Wallace LT, Loffredo JT, Erickson P, Wilson NA, Watkins DI. Simian immunodeficiency virus-specific CD4+ T cells from successful vaccinees target the SIV Gag capsid. Immunogenetics. 2010 Oct; 62(10):701-7. Epub 2010 Sep 2. PMID: 20812010, PMCID: PMC3018234. Martins MA, Wilson NA, Reed JS, Ahn CD, Klimentidis YC, Allison DB, Watkins DI. T-cell correlates of vaccine efficacy after a heterologous simian immunodeficiency virus challenge. J Virol. 2010 May; 84(9):4352-65. Epub 2010 Feb 17. PMID: 20164222, PMCID: PMC2863752.