Proteasome inhibitors block HIV-1 replication by affecting both cellular and viral targets.
HIV-1 has proved to be notoriously difficult to tackle despite the availability of more than 20 clinically approved drugs. The majority of these drugs, however, target viral genes and their continued use will select for drug-resistant strains. Since NF-kappaB signaling is critical for viral replication, we wanted to investigate the effect of proteasome inhibitors on viral gene expression. We herein demonstrate that proteasome and NF-kappaB inhibitors effectively shut down transcription from the HIV-1 LTR-promoter. We further show that replication of HIV-1 in PBMC was severely compromised following treatment with proteasome inhibitors alone or in combination with other antiretroviral drugs. Finally, incubation of PBMC with these drugs reduced expression of IL-2 inducible T cell kinase (Itk), a Tec-family kinase, recently shown to be required for HIV-1 replication. These results suggest that proteasome inhibitors suppress LTR-promoter activity by interfering with cellular targets required for viral replication.
Yu
Liang
L
Department of Laboratory Medicine, Clinical Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. liang.yu@ki.se
Mohanram
Venkatramanan
V
Simonson
Oscar E
OE
Smith
C I Edvard
CI
Spetz
Anna-Lena
AL
Mohamed
Abdalla J
AJ
D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D016325:HIV Long Terminal Repeat / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
D001897:Boronic Acids; D015853:Cysteine Proteinase Inhibitors; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib