title: Proteasome inhibitors act as bifunctional antagonists of human immunodeficiency virus type 1 latency and replication.
abstract: BACKGROUND
  Existing highly active antiretroviral therapy (HAART) effectively controls viral replication in human immunodeficiency virus type 1 (HIV-1) infected individuals but cannot completely eradicate the infection, at least in part due to the persistence of latently infected cells. One strategy that is being actively pursued to eliminate the latent aspect of HIV-1 infection involves therapies combining latency antagonists with HAART. However, discordant pharmacokinetics between these types of drugs can potentially create sites of active viral replication within certain tissues that might be impervious to HAART.
  
  
  RESULTS
  A preliminary reverse genetic screen indicated that the proteasome might be involved in the maintenance of the latent state. This prompted testing to determine the effects of proteasome inhibitors (PIs) on latently infected cells. Experiments demonstrated that PIs effectively activated latent HIV-1 in several model systems, including primary T cell models, thereby defining PIs as a new class of HIV-1 latency antagonists. Expanding upon experiments from previous reports, it was also confirmed that PIs inhibit viral replication. Moreover, it was possible to show that PIs act as bifunctional antagonists of HIV-1. The data indicate that PIs activate latent provirus and subsequently decrease viral titers and promote the production of defective virions from activated cells.
  
  
  CONCLUSIONS
  These results represent a proof-of-concept that bifunctional antagonists of HIV-1 can be developed and have the capacity to ensure precise tissue overlap of anti-latency and anti-replication functions, which is of significant importance in the consideration of future drug therapies aimed at viral clearance.
authors.forename: Leia K
authors.initials: LK
authors.lastname: Miller
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Chiann-Chyi
authors.initials: CC
authors.lastname: Chen
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Russnak
authors.forename: Yacov
authors.initials: Y
authors.lastname: Ron
authors.affiliation: Department of Molecular Pharmacology, Rutgers, The State University of New Jersey - Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA. doughejp@rwjms.rutgers.edu.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Dougherty
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D061988:Proteasome Inhibitors