Proteolytic events of HIV-1 replication as targets for therapeutic intervention

Acquired immunodeficiency syndrome (AIDS) is a worldwide epidemic caused by infection with HIV, a human retrovirus. Proteolysis occurs at many points of the retroviral life-cycle, and these events can be considered as targets for chemotherapy. The most well-known proteolytic action in the retroviral life-cycle is the processing of the Gag and Gag-Pro-Pol polyproteins with the virally encoded protease at the late phase of viral infection. Protease inhibitors, together with reverse transcriptase inhibitors, are important components of the drug combinations currently used to treat HIV patients. The current combination therapy substantially reduced morbidity and mortality in HIV-infected patients. However, these drugs do not allow viral eradication, therefore their long-term use is required, allowing the development of resistance in a large portion of patients. Furthermore, several adverse metabolic side effects have been observed associated with the therapy. Thus, new approaches are required to eradicate HIV infection, which may include targeting of the potential early-phase function of the viral protease, and other crucial proteolytic events of the viral replication, such as the ubiquitin-dependent proteolytic degradation of the unfolded viral proteins as well as the inhibition of envelope protein processing.