HIV-1 disease leads to a gradual loss of CD4 T cells that culminates in immune deficiency and death. While highly active antiretroviral therapy (HAART) can delay this progression, it is associated with significant toxicities and at this time appears to be insufficient to eradicate HIV from the body. Ex vivo expansion and infusion of CD4 and CD8 T cells may help delay the onset of immunodeficiency and enhance immunological control of H1V infection. The first culture system that permitted the long-term expansion of HIV-1 infected T cells in the absence of antiretrovirals used antibody coated magnetic beads. These studies provided the justification for a number of Phase I clinical trials that tested the safety and feasibility of infusing up to 3 x10(10) autologous CD4 T cells back into HIV infected individuals. These studies have raised hope that ex vivo expansion and infusion of T cells will be an effective component of HIV therapy, but they have also revealed a number of limitations that hinder the effectiveness and widespread use of this form of immunotherapy. The main goal of this application is to develop improved culture systems to expand HIV specific CD8 T cells with improved effector functions. Specifically, the experiments in Aim #1 propose to adapt a newly described cell based artificial antigen presenting cell (aAPCs) to expand HIV-specific T cells. These studies will test the hypothesis that effector functions can be restored to these T cells by optimal ex vivo expansion. The experiments described in Aim 2 will explore expanding HIV specific T cells with a broad specificity. Here, MHC expressing aAPC mixed with chemically inactivated patient specific virus and autologous CD8 T cells will be used create an ex vivo generated cellular vaccine. We will compare the ability of cells expanded in this manner to recognize autologously infected T cells to the cells superinfected with references strains such Bal and NL4-3. Successful completion of these aims will pave the way for second generation autologous transfusion trials in which the ability of selected subsets of expanded T cells to fight opportunistic and HIV infection(s) can be measured.
| Varela-Rohena, Angel; Molloy, Peter E; Dunn, Steven M et al. (2008) Control of HIV-1 immune escape by CD8 T cells expressing enhanced T-cell receptor. Nat Med 14:1390-5 |
| Varela-Rohena, Angel; Carpenito, Carmine; Perez, Elena E et al. (2008) Genetic engineering of T cells for adoptive immunotherapy. Immunol Res 42:166-81 |
| Suhoski, Megan M; Golovina, Tatiana N; Aqui, Nicole A et al. (2007) Engineering artificial antigen-presenting cells to express a diverse array of co-stimulatory molecules. Mol Ther 15:981-8 |
| Kovacs, Birgit; Parry, Richard V; Ma, Zhengyu et al. (2005) Ligation of CD28 by its natural ligand CD86 in the absence of TCR stimulation induces lipid raft polarization in human CD4 T cells. J Immunol 175:7848-54 |
