Cellular Immunity in Aging and HIV: Correlates of Protection Janet E. McElhaney, MD Professor of Medicine Allan M. McGavin Chair in Research Geriatrics University of British Columbia Vancouver, BC and Center for Immunotherapy of Cancer and Infectious s Department of Immunology University of Connecticut School of Medicine, Farmington, CT Immune Senescence B APC Viral Vaccines Age IFN-γ, IL-2 2 IL-4, IL-3 7 IL-7 7 3 IL-0, TGF-β
Correlates of Protection: Targeting the appropriate immune response Live-attenuated virus vaccines Stimulate a response that is similar to natural infection Killed virus vaccines Stimulate neutralizing antibodies and CD4+ elper cells but not t CD8+ cytotoxic T lymphocyte responses Replication defective virus-based vaccines Stimulate CD4+ elper and CD8+ cytotoxic T cells responses but poor neutralizing antibody titers Testing responses to vaccination Serologic responses - neutralizing antibody titers or equivalent Cellular immune responses Measure or restimulate virus-specific specific T cell memory T-cell proliferative capacity and correlation with serologic response Pantaleo G and Koup RA. Nature Mediciine 0:806, 2004 Antibody Response to Influenza Vaccination: Correlate of Protection? 000 03-0404 Season Antibody Titer (GMT) 00 0 Flu season Error Bars = Std Error 0 4 0 McElhaney et al. J Immunol 76:6333-9, 2006 2
Evaluation of T Cell Responses * In Vitro Ex Vivo p APC Stimulation: vaccine, peptide, adjuvant live virus PMA/ionomycin viral peptides Assays: ELISPOT, Proliferation Cytokines in PMBC Supernatants Granzyme B in PBMC Lysates Flow Cytometry Chemo/ cytokines Ex Vivo * In Vitro *Murasko et al. Exp Gerontol 37:327-39, 39, 2002 McElhaney et al. J Immunol 76:6333-9, 2006 Changes in CD8+ T cells with aging and HIV infection HIV Non-progressive Memory with costimulatory CD28 Progressive HIV CMV-specific effector CMV End Organ CMV-specific > HIV or EBV-specific Aging CMV+ No CMV IL-2 2 production and proliferative capacity Oligoclonal expansion of CMV-specific are CD28-3
Changes in CD4+ T cells with aging and HIV infection HIV Non-progressive Memory Th IFN-γ,, IL-2 Progressive HIV Effector Th IFN-γ CMV End Organ CMV Driven Expansion Aging 7 Th3 Type of Stimulation Repeated Stimulation Terminal Differentation IFN-γ only Correlates of Protection: Comparisons of HIV and Aging CD4+ T-cell T responses in non-progressive disease HIV-specific similar to EBV- and CMV-specific responses IFN-γ and IL-2 2 production associated with non-progressive disease but decline with aging CD8+ T-cell T responses HIV-specific similar to EBV- and CMV-specific responses IL-2 2 production and proliferative capacity maintained with non-progressive disease but decline with aging Chronic progressive HIV infection Monofunctional T-cell response with high frequencies of virus-specific specific CD4+ and CD8+ T cells that secrete IFN-γ; ; this also occurs with aging Effectiveness of the virus-specific specific immune response Depends more on the quality rather than quantity of CD4+ and CD8+ T cells HIV-specific CD8+ responses in individuals exposed to HIV remain uninfected nfected HIV-specific CD4+ responses associated with virus control Depletion of CD8+ results in loss of virus control and restored with repletion of CD8+ T cells HIV-specific CD4+ and CD8+ preserved in long-term non-progressors Pantaleo G and Koup RA. Nature Mediciine 0:806, 2004 4
IFN-γ : IL-0 Ratio Vaccination and Infection*.6 B/Hong Kong.2 Mean Log IFNγ : IL-0 Ratio.8.4 0 -.4 A/Pan Flu vs. No Flu: IFN-γ:IL :IL-0: P<.000 Error bar: std dev 0 4 0 0 4 0 *Adjusted for ACE, statin,, SMWT : H3N2 vaccine strain A/Wyoming: H3N2 circulating strain Grz B Response: Vaccination and Infection* B/Hong Kong Mean Log Grz B U/mg protein.8.6.4.2 0 A/Pan Flu vs. No Flu: Grz B: P<.000 Error bar: std dev 0 4 0 0 4 0 *Adjusted for ACE, statin,, SMWT : H3N2 vaccine strain A/Wyoming: H3N2 circulating strain 5