VACCINE REGIMENS TO INDUCE CD4+ AND CD8+ T CELLS AGAINST SIV EPITOPES

University Of Wisconsin-Madison, Madison WI

Investigators

Linked publications & trials

Abstract

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 compare four novel vaccine regimens to induce CD4+ and CD8+ T Cells against SIV epitopes. Recent failures in clinical HIV vaccines have underscored the importance of more thoroughly evaluating basic science of HIV as well as testing new vaccine regimens and vectors. In an effort to overcome the limitations of more traditional vector-based vaccines, our laboratory has developed several novel immunization strategies. These new methods will allow us to directly prime specific T cell responses in a manner that previously has been impossible with other vaccine vectors and regimens. This should allow us to dissect the contributions of specific T cell responses in the control of SIV replication- the roles of both subdominant CD8+ T cells and virus-specific CD4+ T cells. In the R21 phase of this grant, we will compare four novel vaccination regimens: peptide-pulsed dendritic cells, peptide-conjugated nanobeads, peptide-pulsed PBMC, and SIV peptides fused to a Hepatitis B core antigen (HBcAg) carrier gene. SUBPROJECT PROGRESS: We have completed vaccinating animals in groups one and two of the R21 phase. These animals received autologous dendritic cells pulsed with three Mamu-DR[unreadable]w*606-restricted CD4 epitopes and primed with either autologous PBMC pulsed with the same epitopes or peptide-conjugated nanobeads. Two weeks after the final boosts, no animals made any detectable epitope-specific CD4+ T cell responses as detected by ELISPOT or ICS. The HBcAg vectors were completed by Dr. Deborah Fuller with each of the selected Mamu-A*01-restricted CD8 epitopes inserted into individual vectors. Six Mamu-A*01+ animals, groups three and four, received four doses of the HBcAg vector;however, unfortunately it was later discovered that the gene gun administering these vaccines was not optimally functioning. We're going to give all six animals a fifth HBcAg dose. After the fourth dose, no animals made any detectable epitope-specific CD8+ T cell response;however, they did respond well to Hepatitis peptide provided by Dr. Fuller indicating that they did receive some doses of the vaccine. Once given a fifth dose, we will move into the boost of these groups. One group will receive autologous PBMC pulsed with each of the A*01 epitopes, while the other group will receive the A*01 epitopes conjugated to nanobeads. We will request a one year no-cost extension for this project. For the CD4 Aim of the R21, we will repeat the dendritic cell prime-nanobead boost using a longer dendritic cell isolation protocol. Additionally, we will make DNA and Adenovirus vectors containing the three CD4 epitopes. We will vaccinate animals with these constructs in the hope of eliciting epitope-specific CD4+ T cell responses. Lastly, if the HBcAg prime-PBMC/nanobead boost regimens are unsuccessful, we will also DNA prime-Adenovirus boost animals with the A*01 epitopes to successfully elicit epitope-specific CD8+ T cell responses. This research uses Animal Services and Research Services.