In this R01 renewal application, we propose to continue our work examining the role of T cell function in the control of acute and chronic HIV infection, for the purpose of developing meaningful correlates of protection in HIV infection that can be applied to HIV vaccine development. Here we will focus on the regulation of CD8+ T effector cell and CD4+ T helper type-1 cell function,by the transcription factors T-bet and eomesodermin (eomes), in order to understand the failings of the HIV-specific T cell immune response during acute and chronic HIV infection. We will further study the ability of different vaccine and adjuvant strategies to stimulate the expression of these key transcription factors. Previously we have shown that 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. Our preliminary data demonstrates that although a massive (40-75% of T cells) acute effector CD8+ T cell response is raised during acute HIV infection, these responses cannot be maintained, perhaps due to their failure to upregulate and properly localize T-bet or eomes within responding cells, ultimately resulting in failure to control viremia. During this sam period, T-bet expressing HIV-specific CD4+ T cells are lost within weeks of infection, suggesting a rapid loss of T helper type 1 responses critical for the generation and maintenance of effective CD8+ T cell responses and antibody responses. Importantly however, T-bet expression is maintained in both HIV-specific CD4+ and CD8+ T cells in HIV elite controllers, suggesting that these responses play a key role in effective HIV-specific immune responses. Based upon these premises, we hypothesize a successful HIV vaccine will require stimulation of T-bet/eomes dependent HIV-specific CD8 effector and CD4 Th1 responses in order to mediate clearance or control of initial viremia. In this application we will therefore focus on defining effector CD8+ ad CD4 Th1 T cell responses in the control of HIV viremia, the transcriptional regulation of these responses, and whether these types of responses can be induced by different vaccine/adjuvant strategies.
In Aim 1 we will define the relationship between CD8+ T cell effector function and T-bet/eomes expression and localization in HIV acute, chronic, and nonprogressive infection and how they relate to long-term control of viremia.
In Aim 2, we will define the induction and maintenance of T-bet/eomes expressing CD4+ Th1 T cells in acute, chronic, and nonprogressive infection, and how these directly relate to the quality of the HIV-specific CD8+ T cell response and maintenance of CD8+ T cell effector function. Finally, in Aim 3, we will define the potential for T-bet and eomes to be modulated within human and rhesus macaque CD4+ and CD8+ T cells by current HIV vaccine and adjuvant strategies for application to both prophylactic and therapeutic (cure-based) HIV vaccine development.
CD8+ T cell effector activity and CD4+ Th1 helper cell responses are key components of effective HIV immune responses, activity which is controlled in part by two transcription factors, T-bet and eomesodermin. Here, we will examine the modulation, expression and intracellular localization of these transcription factors in the context of HIV infection, and after administration of different adjuvants in the context of HIV vaccines. These studies will help to identify important correlates of protection in HIV infection that can be used to improve the protective quality of HIV vaccine-stimulated CD4+ and CD8+ T cells.
|Pombo, Carolina; Wherry, E John; Gostick, Emma et al. (2015) Elevated Expression of CD160 and 2B4 Defines a Cytolytic HIV-Specific CD8+ T-Cell Population in Elite Controllers. J Infect Dis 212:1376-86|
|Herati, Ramin Sedaghat; Reuter, Morgan A; Dolfi, Douglas V et al. (2014) Circulating CXCR5+PD-1+ response predicts influenza vaccine antibody responses in young adults but not elderly adults. J Immunol 193:3528-37|
|Buggert, Marcus; Tauriainen, Johanna; Yamamoto, Takuya et al. (2014) T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection. PLoS Pathog 10:e1004251|
|Frentsch, Marco; Stark, Regina; Matzmohr, Nadine et al. (2013) CD40L expression permits CD8+ T cells to execute immunologic helper functions. Blood 122:405-12|
|Demers, Korey R; Reuter, Morgan A; Betts, Michael R (2013) CD8(+) T-cell effector function and transcriptional regulation during HIV pathogenesis. Immunol Rev 254:190-206|
|McLane, Laura M; Banerjee, Pinaki P; Cosma, Gabriela L et al. (2013) Differential localization of T-bet and Eomes in CD8 T cell memory populations. J Immunol 190:3207-15|
|Reuter, Morgan A; Pombo, Carolina; Betts, Michael R (2012) Cytokine production and dysregulation in HIV pathogenesis: lessons for development of therapeutics and vaccines. Cytokine Growth Factor Rev 23:181-91|
|van Montfrans, Joris M; Hoepelman, Andy I M; Otto, Sigrid et al. (2012) CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia. J Allergy Clin Immunol 129:787-793.e6|
|Hersperger, Adam R; Martin, Jeffrey N; Shin, Lucy Y et al. (2011) Increased HIV-specific CD8+ T-cell cytotoxic potential in HIV elite controllers is associated with T-bet expression. Blood 117:3799-808|
|Makedonas, George; Betts, Michael R (2011) Living in a house of cards: re-evaluating CD8+ T-cell immune correlates against HIV. Immunol Rev 239:109-24|
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