Immunotherapy-induced cytotoxic T follicular helper cells reduce numbers of retrovirus-infected reservoir cells in B cell follicles

Antiretroviral therapy (ART) transformed HIV from a life-threatening disease to a chronic condition. However, eliminating the virus remains an elusive therapy goal. For several decades, Friend virus (FV) infection serves as a murine model to study retrovirus immunity. Similar to HIV, FV persists at low levels in lymph nodes B cell follicles avoiding elimination by immune cells. Such immune-privileged reservoirs 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, we explored immunotherapy to induce cytotoxic Tfh, which are rarely found under physiological conditions. The TNF receptor family member CD137 was first identified as a promising target for cancer immunotherapy. We demonstrated that FV-infected mice treatment with alpha CD137 antibody resulted in an induction of the cytotoxic program in Tfh. The therapy significantly increased numbers of cytotoxic Tfh within B cell follicles and contributed to viral load reduction. Moreover, alpha CD137 antibody combined with ART delayed virus rebound upon treatment termination without disturbing the lymph node architecture or antibody responses. Thus, alpha CD137 antibody therapy might be a novel strategy to target the retroviral reservoir and an interesting approach for HIV cure research. Despite the development of potent antiretroviral therapy, elimination of the HIV reservoir from lymph nodes remains elusive. The main reason is that lymph nodes are an immune privileged site in which cytotoxic T cell activity is restricted. We used the Friend retrovirus (FV) mouse model to develop a novel therapy approach that targets the retroviral reservoir in lymph nodes. Immunotherapy with CD137 activating antibodies induced a cytotoxic program in follicular CD4+ T cells, which improved their killing capacity and resulted in a reduction of the FV reservoir in lymph nodes. Antibody treatment combined with antiretroviral therapy delayed virus rebound upon treatment termination without disturbing the lymph node architecture or antibody responses to unrelated antigens. Thus, alpha CD137 antibody therapy might be a novel strategy to target the retroviral reservoir in lymph nodes and an interesting approach for HIV cure research.