Eliminating the retroviral reservoir: Therapeutic induction of cytotoxic follicular T helper cells that kill infected cells in B cell follicles

• Applicant: Professor Dr. Ulf Dittmer, since 2/2024
• Subject Area: Immunology ; Virology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513559745

Since antiretroviral therapy (ART) has been introduced to the clinic, infections with the Human Immunodeficiency Virus (HIV) was transformed from a life-threatening disease to a chronic manageable condition. However even for individuals on ART, the goal to eliminate the virus or reach functional cure continues to be elusive. According to recent studies, HIV-infected CD4+ T cells remain in B cell follicles of lymph nodes where they persist during ART. Cytotoxic CD8+ T lymphocytes are not eligible to enter B cell follicles and are therefore unable to kill these infected targets. Thus, HIV-infected follicular helper T cells, which express the receptor and co-receptor for HIV, form inaccessible reservoirs in lymph nodes and spleen that can so far not be eradicated by any clinically used or experimentally tested antiretroviral therapy. For several decades, Friend virus (FV) infection serves as a murine model to study retroviruses and their interaction with cells of the immune system. Similarly to HIV, FV is not completely eliminated by immune cells during the acute phase of infection, but persists in low levels in B cell follicles of the spleen and lymph nodes as viral reservoir. Such reservoirs are immune privileged sites that exclude cytotoxic T cells from entry. However, CXCR5+ T cells are permitted to traffic through germinal centers. This marker is predominantly expressed by CD4+ follicular helper T cells (Tfh). Therefore, exploring therapeutic interventions to augment the cytotoxicity of CD4+ CXCR5+ Tfh, is an interesting novel approach to eradicate retroviruses from their reservoir. Despite the fact that immunotherapy is widely studied and used for cancer eradication, the idea to utilize its beneficial effects to combat viral reservoirs was not under careful investigation. In our project, we will define the potential of agonist αCD137 therapy, an antibody that is known to initiate T cell cytotoxicity, in inducing cytotoxic Tfh cells that eliminate retroviral reservoirs within murine and human lymphoid organs.

• DFG Programme: Research Grants
• International Connection: Canada
• Cooperation Partner: Professorin Kerry J. Lavender, Ph.D.
• Ehemalige Antragstellerin: Dr. Anna Malyshkina, until 2/2024