Lymphoid tissue is the key site for the initial seeding, dissemination, and long-term maintenance of the HIV reservoir. As such, understanding those T cell properties and mechanisms required for control and elimination of HIV directly within lymphoid tissue are of critical importance to the HIV cure, eradication, and vaccine agenda. The central question underlying this proposal is whether HIV-specific CD8+ and CD4+ T cells in the lymph node (LN) have or can acquire the functional capabilities necessary to control or eliminate HIV infected cells. These studies are predicated on the concept that cytotoxic CD8+ (and CD4+) T cells are normally absent from the lymph node in HIV- subjects or those without underlying inflammatory conditions. Intuitively, this makes biological sense: why would cytotoxic T cells be wanted in a LN? Cytotoxic T cells (either CD8+ or CD4+) in the LN would function in part to eliminate antigen presenting cells, thereby dampening immune responses. However, in HIV infection, HIV vaccines, and especially HIV cure-based strategies, cytotoxic HIV- specific CD8+ T cells within the LN would be needed to control or eliminate virally infected CD4+ T cells. Our preliminary data show the presence of dysregulated perforin+ HIV-specific CD8+ T cells in the LN from chronically infected subjects, with very low expression of CXCR5, a marker required for entry into the lymphoid follicle, where HIV-infected CD4+ T cells are concentrated. Unexpectedly, antiretroviral therapy appears to reverse this, with heightened CXCR5 expression on LN CD8+ T cells, but lower levels of perforin. This is opposite of what one would want as the kill component of an HIV shock and kill cure strategy. Our findings overall indicate that LN CD8+ T cells have fundamentally different functional abilities compared to the conventional wisdom driving the HIV cure and vaccine field. These considerations suggest that were an effective anti-HIV cytolytic T cell response present, it would not target the LN HIV reservoir in the majority of HIV-infected people. To address these issues, we will examine LN T cell responses against HIV in subjects with progressive HIV infection, ART-treated HIV infection, and elite control of HIV infection. Our studies will provide critical information for therapeutic manipulation, engineering, or vaccine-mediated strategies designed to induce HIV-specific CD8+ T cells capable of homing to appropriate regions of the LN in order to eliminate HIV reservoirs.
In Aim 1 we will define the effect of antiretroviral therapy on LN total and HIV-specifc CD8+ and CD4+ T cells compared to HIV infected chronic progressors and elite controllers.
In Aim 2, we will determine whether LN- and PBMC-derived CD8+ and CD4+ T cells from ART-treated HIV-infected individuals have effective cytolytic activity. Finally, in Aim 3, we will determine the effect of ART on LN CD8+ and CD4+ HIV-specific T cell transcriptional regulation, activation, cytotoxic properties, and LN retention/egress markers after activation.
CD4+ T cells within lymphoid tissue throughout the body represent the major site of HIV infection and the long-term HIV reservoir that prevents the development of an HIV cure and hampers vaccine development strategies. CD8+ T cell activity is thought to be responsible for controlling HIV replication, but our preliminary data indicates tht this activity is dysfunctional within lymphoid tissue. This proposal will define the function and dysfunction of lymphoid tissue CD8+ T cells in order to define strategies for eliminating HIV infection.
|Wendel, Ben S; Del Alcazar, Daniel; He, Chenfeng et al. (2018) The receptor repertoire and functional profile of follicular T cells in HIV-infected lymph nodes. Sci Immunol 3:|
|Steblyanko, Maria; Anikeeva, Nadia; Buggert, Marcus et al. (2018) Assessment of the Synaptic Interface of Primary Human T Cells from Peripheral Blood and Lymphoid Tissue. J Vis Exp :|
|Noyan, Kajsa; Nguyen, Son; Betts, Michael R et al. (2018) Human Immunodeficiency Virus Type-1 Elite Controllers Maintain Low Co-Expression of Inhibitory Receptors on CD4+ T Cells. Front Immunol 9:19|
|Voillet, Valentin; Buggert, Marcus; Slichter, Chloe K et al. (2018) Human MAIT cells exit peripheral tissues and recirculate via lymph in steady state conditions. JCI Insight 3:|
|Alvarado-de la Barrera, Claudia; Reyes-Terán, Gustavo (2017) Confusion in the Study of Immune Reconstitution Inflammatory Syndrome. Pathog Immun 2:126-137|
|Reuter, Morgan A; Del Rio Estrada, Perla M; Buggert, Marcus et al. (2017) HIV-Specific CD8+ T Cells Exhibit Reduced and Differentially Regulated Cytolytic Activity in Lymphoid Tissue. Cell Rep 21:3458-3470|
|Petrovas, Constantinos; Ferrando-Martinez, Sara; Gerner, Michael Y et al. (2017) Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies. Sci Transl Med 9:|