An inhibitor of HIV-1 protease modulates proteasome activity, antigen presentation, and T cell responses.
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.
André
P
P
Institut Nationale de la Santé et de la Recherche Médicale U98X, Ecole Normale Supérieure, 46 rue d'Italie, 69364 Lyon Cedex 07, France.
Groettrup
M
M
Klenerman
P
P
de Giuli
R
R
Booth
B L
BL
Cerundolo
V
V
Bonneville
M
M
Jotereau
F
F
Zinkernagel
R M
RM
Lotteau
V
V
D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005805:Genes, MHC Class I / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000201:enzymology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D007111:Immunity, Cellular; D008216:Lymphocytic Choriomeningitis / Q000188:drug therapy* / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D019438:Ritonavir / Q000494:pharmacology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*
D017320:HIV Protease Inhibitors; D015395:Histocompatibility Antigens Class I; D009097:Multienzyme Complexes; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D019438:Ritonavir