Recently we demonstrated that T-bet expression in human CD8+ T cells is directly correlated to CD8+ T cell effector function. In chronic HIV infection, low expression of T-bet within HIV-specific CD8+ T cells is associated with poor effector CD8+ T cell responses and a failure to control HIV viremia. Furthermore, our preliminary data demonstrates that despite a massive (40-75% of T cells) acute effector CD8+ T cell response during acute HIV infection, these responses cannot be maintained and ultimately result in failure to durably control HIV viremia perhaps due dysregulation of T-bet. HIV specific CD4+ T cells during acute HIV infection also upregulate T-bet (as is required for Th1 function), but lose this expression within weeks of infection. This loss likely has severe ramifications on the proper programming, maturation, and maintenance of HIV-specific CD8+ T cell effector function that is critical for long-term control of HIV viral load. Here, we will address these concepts in the rhesus macaque model in order to address two hypotheses: 1) we hypothesize that high T- bet expression by SIV/HIV-1 specific CD8+ T cells enables functionally protective responses against viral replication and subsequent disease progression, and that the failure to express adequate T-bet leads to loss of effector function and functional exhaustion, and 2) that rapid loss of T-bet mediated CD4+ T cell Th1 responses will fundamentally alter subsequent T cell help necessary for proper HIV-1-specific CD8+ T cell development and maintenance of effector and memory function.
In Aim 1, we will determine the kinetics of T-bet expression within SIV-specific CD4+ and CD8+ T cells during acute SIV infection, and the relationship between these functional properties and the propensity to induce immune escape. Animals will be serially necropsied during acute SIV infection in order to assess these factors within multiple tissue compartments.
In Aim 2, we will then explore the role of CD4+ T cell help in promoting optimal T-bet expressing CD8+ T cells. We will approach this in two ways~ first we will preserve CD4+ T cell function through early antiretroviral therapy, and second we will deplete CD4+ T cells prior to SIV challenge. In both approaches we will monitor the resultant effects upon the CD8+ T cell compartment with a particular focus on T-bet expression. We will also characterize the propensity to induce immune escape in these situations, and more broadly assess CD8+ T cell function using microarray analysis. Finally, in Aim 3, we will conduct an SIV challenge study to define the role of T-bet expression in SIV-specific CD4+ T and CD8+ T cells in predicting elite control or disease progression in the Mamu B*08/B*17 model of HIV elite control. Together, these complementary Aims will define the importance of T-bet in protective CD4+ and CD8+ T cell responses in HIV/SIV infection, and provide key information on protective T cell functional programming for HIV vaccine development.
CD4+ and CD8+ T cells play critical roles in the control of HIV infection. CD4+ T cells provide help to CD8+ T cells and B cells to enhance their anti-HIV properties. CD8+ T cells are able to eliminate virally infected cells. These activities are controlled in part by the transcription factor, T-bet. Here, we will examine the role of T-bet as key mediator of protective CD4+ and CD8+ T cell responses in the context of SIV infection. These studies will help to identify important correlates of protection in SIV infection that can be used to for the further development of an effective HIV vaccine.
