The ubiquitin-proteasome system in HIV replication: potential targets for antiretroviral therapy.
Since the discovery of HIV approximately 20 years ago, more than 60 million individuals have been infected, and AIDS still remains one of the most devastating diseases humankind has ever faced. Unfortunately, there is little hope that an effective vaccine will be developed in the near future. Current antiretroviral treatment is based on drugs that either target the viral enzymes (protease and reverse transcriptase) or the attachment and entry of the virus. Although the introduction of highly active antiretroviral therapy in the mid-1990s has led to a profound reduction in HIV-related morbidity and mortality, the complete eradication of the virus from infected individuals has never been achieved. In addition, these antiviral drugs can induce serious adverse effects, particularly when administered in combination over prolonged treatment periods. A further drawback to these treatments is that with the high mutation rate of HIV, drug-resistant mutants are evolving, particularly when antiretroviral treatment only suppresses virus replication to marginal levels in latently infected cells making up the virus reservoirs in vivo. Cellular genes have much lower mutation rates, and drug-mediated modulation of specific cellular pathways represents an attractive antiviral strategy. Recent findings showing that proteasome inhibitors interfere with budding, maturation and infectivity of HIV have triggered intensive investigation of the hitherto unappreciated function of the ubiquitin-proteasome system in HIV replication. It was also observed that, like several other retroviruses, HIV-1 virions contain a small amount of mono-ubiquitinylated Gag proteins. Currently, two E3-type ubiquitin ligases, in addition to one E3-like protein, have been identified as regulators of HIV budding. These ligases might represent interesting targets for therapeutic intervention.
Klinger
Patricia P
PP
University of Erlangen-Nuremberg, Institute of Clinical and Molecular Virology, Schlossgarten 4, 91054 Erlangen, Germany.
Schubert
Ulrich
U
D000818:Animals; D044966:Anti-Retroviral Agents / Q000008:administration & dosage* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D061988:Proteasome Inhibitors; D025801:Ubiquitin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D044966:Anti-Retroviral Agents; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex