Maintaining the balance: costimulatory TNFRs and control of HIV

Several TRAF binding members of the TNFR family are potent costimulators of lymphocyte responses making them attractive candidates for immunotherapy of HIV. On the other hand, increased TNFR family signaling can also promote HIV replication as well as generalized immune system activation thereby contributing to the pathogenesis of HIV infection. Thus, TNFR family signaling must be carefully controlled to avoid pathology. TNF/TNFR family members are tightly regulated at the level of their cell surface expression. In addition, recent evidence suggests that during chronic infection signaling by the TNFR family member 4-1BB is attenuated due to loss of the signaling adaptor TRAF1. Exploiting TNFR family members for HIV therapy will require a precise understanding of their in vivo regulation and a targeted approach to ensure improved antigen specific responses without exacerbating generalized immune activation and collateral damage.