Cytolytic CD4 T cells - Defining potential strategies for therapeutic HIV vaccines

• Applicant: Professor Dr. Hendrik Streeck
• Subject Area: Virology ; Immunology
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 405772562

Once HIV establishes infection, the virus persists indefinitely as an integrated part of the genome in a small population of latently infected CD4+ T cells. Cure or eradication attempts have so far failed and HIV remains a lifetime economic, psychological and medical burden for infected individuals. It has been demonstrated that the lymph node harbors high levels of infected CD4 T cells and that in particular T follicular helper (Tfh) cells within the lymphoid B cell follicle harbor high levels of HIV infection. Interestingly, recent studies demonstrated that the location within the B cell follicle is relatively void of CD8 T cells and leaves infected CD4 T cells unseen by CD8 T cell recognition. Thus, a major hurdle impeding the immune system to eradicate HIV is that HIV-specific CD8 T cells do not enter this microanatomical location. The overarching hypothesis is that targeted reprogramming of either Tfh cells to induce a cytolytic program or peripheral cytolytic T cells to enter the follicle will be a critical tool to purge HIV’s reservoir.We previously demonstrated that HIV-specific cytolytic CD4 T cells emerge early during acute HIV infection and are associated with early viral control and long-term disease progression. These cells are phenotypically, functionally and transcriptionally distinct from Th1 HIV-specific CD4 T cells. Moreover, we were recently able to show that TGFβ signaling is inhibiting the cytotoxic program in T cells and are currently determining further factors that drive the cytolytic program of naïve CD4 T cells. We will therefore first analyze the presence and frequency of T follicular helper cells with a cytolytic program (termed: Tfc) within HIV infected and uninfected individuals and will determine the ability of peripheral cytotoxic T cells (termed: CTL) to enter the follicle. We will determine under which conditions the induction of Tfc cells occurs and CTL gain the ability to enter the follicle in vitro and after vaccination. Lastly, we will test in a proof-of-principle study whether therapeutic vaccines can specifically reprogram Tfh cells to induce a cytolytic program to act against latently HIV infected cells in the reservoir.

• DFG Programme: Research Grants