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Name:	John D. Altman
Position:	Associate Professor of Microbiology and Immunology Affiliate Scientist of Yerkes National Primate Research Center Associate Professor of Emory Vaccine Center
Degree:	Ph.D., University of California, 1991
Programs:	IMP, Full Member
Phone:	404 727-5981
Address:	Yerkes Natl Primate Ctr, 954 N. Gatewood Dr., 2440/001/1AA
Email:	john.altman@emory.edu
Research Descriptions:
Short:	T-cell immune responses to HIV infection; vaccine development; development of T-cell memory.
Long:	During my postdoctoral work with Dr. Mark Davis at Stanford University, I developed an important new technology to directly identify antigen-specific T cells by staining with tetrameric forms of soluble MHC/peptide complexes that have enhanced avidity for cells bearing specific T cell antigen receptors (TCR). Since coming to Emory, I have developed several research programs, all centered around use of this new technology to investigate many aspects of CD8+ T cell mediated immune responses to viral infections. These include basic studies in mouse models designed to answer questions about the factors contributing to the development of antigen-specific T cell repertoires, clinically relevant studies to assess immune function in HIV-infected individuals on potent anti-retroviral therapy, and applied studies to assess AIDS vaccine efficacy in a rhesus macaque model. Together with Rafi Ahmed, we are employing the LCMV model to investigate the basis of T cell memory and the development of the LCMV-specific T cell repertoires. In B6 mice, there are three immunodominant CD8+ T cell epitopes within LCMV, all restricted by H-2Db; we have successfully prepared and tested MHC tetramers for each of these epitopes. For the strongest epitope, the NP396 peptide, costaining with Vb antibodies shows that the primary response is diverse , with the participation of at least four distinct TCR Vb regions. We have also shown that there are both conserved and non-conserved responses, suggesting that we will have to follow repertoire development over time in individual mice. Studies of LCMV infection in BALB/c mice show very similar results. The Vb repertoire specific for the single immunodominant epitope NP118 is diverse and not completely conserved between individual mice. We also plan to investigate the lifespan of memory T cells in these non-transgenic mice, and we have developed methods to costain T cells with MHC tetramers and antibodies to detect incorporation of BrdU. The tetramers were originally developed to study CD8+ responses to HIV, and the initial reagents were based on two HIV-peptide complexes with HLA-A*0201. The most surprising finding of those studies was that the frequency of CD8+ T cells for a specific epitope was as high as 2% of all CD8+ T cells. We plan to follow up these studies to examine the effects of highly active antiretroviral therapy (HAART) on the frequency and function of HIV-specific CD8+ T cells. The questions that we will address concern the contribution of chronic antigen stimulation to maintaining the specific cells at high frequency and the effect it has on function. In many patients with high viral burdens, we have found that the HIV-specific CD8+ T cells die upon in vitro stimulation with peptide and IL2. We plan to investigate this further to determine if this antigen induced cell death is relevant in vivo and if it represents an important mechanism used by the virus to escape the immune response. Finally, we plan to use the MHC tetramers to assess vaccine development studies in the rhesus macaque model; this work is part of a program project grant from the Emory Vaccine Center, led by Dr. Harriet Robinson. Together with a team including Drs. Brian Barber and Kelly MacDonald from the University of Toronto, Francois Villinger from Emory, and Janet McNicholl from the CDC, we plan to map CD8+ T cell epitopes from SIV and SHIV viruses in the macaques in our colony at the Yerkes Primate Center. We will also receive important information from Dr. David Watkins at the Wisconsin Primate Center, who will be conducting parallel studies. Once the relevant epitopes are mapped, we will prepare tetramers based upon the macaque MHC molecules which present them, and we will study the effectiveness of a number of planned vaccination strategies at inducing sizable SHIV-specific CD8+ T cell responses. These studies hope to provide insight into the potential correlates of protective immunity to SHIV infection in macaques, with potential extension of the model to humans.