Early localized SIV-specific CD8 T cells response to pathogenic SIV is correlated with successful SIV vaccine

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 SIVDeltanef 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 SIVDeltanef 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.