AN INHIBITOR OF HIV-1 PROTEASE MODULATES PROTEASOME ACTIVITY, ANTIGENPRESENTATION, AND T-CELL RESPONSES

Inhibitors of the protease of HIV-1 have been used successfully for th e treatment of HIV-l-infected patients and AIDS disease. We tested whe ther these protease inhibitory drugs exerted effects in addition to th eir antiviral activity. Here, we show in mice infected with lymphocyti c choriomeningitis virus and treated with the HIV-1 protease inhibitor ritonavir a marked inhibition of antiviral cytotoxic T lymphocyte (CT L) activity and impaired major histocompatibility complex class I-rest ricted epitope presentation in the absence of direct effects on lympho cytic choriomeningitis virus replication. A potential molecular target was found: ritonavir selectively inhibited the chymotrypsin-like acti vity of the 20S proteasome. In view of the possible role of T cell med iated immunopathology in AIDS pathogenesis, the two mechanisms of acti on (i.e., reduction of HIV replication and impairment of CTL responses ) may complement each other beneficially. Thus, the surprising ability of ritonavir to block the presentation of antigen to CTLs may possibl y contribute to therapy of HIV infections but potentially also to the therapy of virally induced immunopathology, autoimmune diseases, and t ransplantation reactions.