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Inhibitors of the protease of HIV-1 have been used successfully for the treatment of HIV-1-infected patients and AIDS disease. We tested whether these protease inhibitory drugs exerted effects in addition to their antiviral activity. Here, we show in mice infected with lymphocytic choriomeningitis virus and treated with the HIV-1 protease inhibitor ritonavir a marked inhibition of antiviral cytotoxic T lymphocyte (CTL) activity and impaired major histocompatibility complex class I-restricted epitope presentation in the absence of direct effects on lymphocytic choriomeningitis virus replication. A potential molecular target was found: ritonavir selectively inhibited the chymotrypsin-like activity of the 20S proteasome. In view of the possible role of T cell-mediated immunopathology in AIDS pathogenesis, the two mechanisms of action (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 possibly contribute to therapy of HIV infections but potentially also to the therapy of virally induced immunopathology, autoimmune diseases, and transplantation reactions.

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

27/10/1998

Volume

95

Pages

13120 - 13124

Keywords

Animals, Cysteine Endopeptidases, Genes, MHC Class I, HIV Protease Inhibitors, HIV-1, Histocompatibility Antigens Class I, Humans, Immunity, Cellular, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Multienzyme Complexes, Proteasome Endopeptidase Complex, Ritonavir, T-Lymphocytes, T-Lymphocytes, Cytotoxic