Live-attenuated lentivirus vaccines are the most effective in inducing protection against subsequent challenge with pathogenic lentiviruses. For example, infection with live-attenuated simian immunodeficiency viruses (SIVs) including nonpathogenic simian-human immunodeficiency virus (SHIV) 89.6, and SIV∆nef in macaques provides protection against subsequent challenge with highly pathogenic strains of SIV. The mechanism by which live-attenuated SIVs induce protection is not well understood. My central hypothesis is that an early SIV-specific CD8 T cell response in lymph nodes and at the site of infection is responsible for the protection induced from live-attenuated SIV vaccines. The rationale for this hypothesis stems from our previous studies showing that SIV disseminates throughout the body by one week post-infection but SIV-specific CD8 T cell responses are too late and not detected in situ until the second and third weeks post-infection. For the present study, rhesus macaques were immunized intravenously with live non-pathogenic SHIV89.6, or SIV∆nef and then challenged intravaginally with pathogenic SIVmac239, or SIVmac251. Using the experimental approach of in situ tetramer staining combined with immunohistochemistry, confocal microscopy and quantitative image analyses, I determined: 1) localization and quantification of virus-specific CD8 T cells; 2) phenotypic changes in lytic granule contents of virus-specific CD8+ T cells; and 3) virus-specific CD8 T cells interacting with CD83+cells in tissues from these animals. My main results show that an early but not necessarily robust SIV-specific CD8 T cell response localized to lymph nodes and genital tissues correlated with protection in these animals. In addition, the majority of SIV-specific CD8 T cells that I observed in vaccinated animals showed little to no perforin expression, compared to cells from non-vaccinated and pathogenic SIV-infected animals. Lastly, I also observed an increase in the interaction of vaccine-induced SIV-specific T cells with CD83+ dendritic cells after pathogenic SIV challenge in immunized animals. These results indicate that vaccine-induced protection correlates with early localized SIV-specific CD8 T cells that show little to no perforin expression at the portal of viral entry and lymph nodes. Additionally my studies indicate that vaccine-induced protection correlates with increased interactions of SIV-specific CD8 T cells with mature dendritic cells. These studies provide a better understanding of immune correlates involved in the protection afforded by live-attenuated SIV vaccines, and provide insights into what is needed to create a successful HIV vaccine.
University of Minnesota Ph.D. dissertation. January 2010. Major: Comparative and Molecular Biosciences. Advisor: Pamela Jo Skinner. 1 computer file (PDF); xii, 128 pages.
Hong, Jung Joo.
Early localized SIV-specific CD8 T cells response to pathogenic SIV is correlated with successful SIV vaccine..
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