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HIV can lie dormant in cells, evading immune detection until it suddenly roars to life without warning and begins replicating furiously. Salk Institute researchers discovered a small molecule-JIB-04 that destroys the HIV protein-Tat, responsible for revving the virus. The molecule is too toxic to serve as a therapy for HIV, reveals proteins in host cells that can potentially target Tat and halt this replication process.
The level of Tat determines whether or not virus can reactivate a virus from latency, JIB-04 cannot be used clinically, but it can show an important part of how Tat levels are determined by a pair of enzymes in the host cell. Like all viruses, HIV-1-the common form of HIV enters the body and uses the host’s cellular machinery to copy the viral genetic material and spread from cell to cell. Tat kicks copying into high gear when conditions are favorable, revving up the machinery a thousandfold.
The application of the DiffPOP technique to identify drug/ protein interactions enabled the identification of a completely unexpected insight into the biology of HIV. The DiffPOP results showed that JIB-04 was binding to two of the host cells’ enzymes (SHMT2 and BRCC36) whose job is to rescue proteins that have been targeted for disposal. Some enzymes flag proteins as cellular “trash”; others remove the flags, thereby saving those proteins from destruction.
The compound interfered with the ability of these proteins to protect Tat, enabling the cell to destroy Tat and keep the virus in its latent state. Further tests confirmed their hypothesis: in cells not treated with JIB-04, but in which the two enzymes were disabled through molecular methods, Tat levels also went down. Additionally, in cells that were treated with JIB-04 as well as ones in which the two enzymes were disabled, Tat was flagged for degradation at high levels, which also suggested that the enzymes were responsible for flag removal.
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