Correlates of cytotoxic T lymphocyte vaccine-induced control against Simian immunodeficiency virus (SIV)

Abstract

There is an urgent need to develop a successful HIV vaccine. Despite continuous efforts, development of a protective HIV-1 vaccine remains a big challenge. HIV-1/SIV-specific CD8+ T cells play a pivotal role in the control of virus replication. During chronic HIV-1 and SIV infections, virus replication is most concentrated within lymphoid B cell follicles, whereas virus-specific CD8+T cells concentrate in extrafollicular areas of secondary lymphoid tissues and tend to be excluded from follicular areas. My thesis focuses on identifying immune correlates of control associated with successful CD8+T cell-based SIV vaccines to help understand what is required to develop a successful HIV vaccine. My central hypothesis is that vaccine-induced control will be associated with induction of an early SIV-specific CD8+T cell response at the portal of viral entry and in lymphoid tissues and also with induction of high levels of virus-specific CD8+T cells in follicular areas of lymphoid tissues. I determined the location, abundance, and phenotype of virus-specific CD8+T cells and the abundance of virus-infected cells in vaccinated and unvaccinated rhesus macaques. Freshly collected unfixed tissue samples were analyzed using in situ tetramer staining combined with immunohistochemistry, in situ hybridization, confocal imaging, and quantitative image analysis. I found that vaccine-induced control was associated with induction of virus-specific CD8+T cells before challenge with pathogenic SIV. Virus-specific CD8+T cells expanded rapidly after challenge and resulted in high effector (SIV-specific CD8+T cells) to target (SIV-infected cells) ratios at the portal of viral entry and in lymph nodes. Additionally, vaccine-induced control correlated with the induction of high follicular: extrafollicular ratio of virus-specific CD8+T cells in lymphoid tissues. Moreover, this control correlated with induction of SIV-specific CD8+T cells that expressed little perforin and with SIV-specific CD8+ T cells in which perforin was exclusively localized to the cell membrane in lymphoid tissues. These cells are likely effector memory T cells with an immediate killing ability. These findings provide a better understanding of the immune correlates of CD8+T cell-based vaccine-induced control against SIV and provide understating of what is needed to create an effective HIV vaccine.