Scientists have discovered that a cellular enzyme helps ferry HIV genetic instructions out of the cell nucleus where they can then be translated into proteins to begin their most destructive work.
The cellular enzyme represents a potential new target for developing improved HIV drugs, say the researchers from the National Institute of Allergy and Infectious Diseases (NIAID) and the McGill University AIDS Center.
Kuan-Teh Jeang, M.D., Ph.D., of NIAID led the research team reporting their discovery in the Oct. 29 issue of Cell.
"This finding provides new insights into a crucial step in HIV replication," says Anthony S. Fauci, M.D., director of NIAID. "The discovery also provides an attractive target for drug development which, if successful, might in time give us a completely new type of HIV drug that circumvents the problem of drug resistance."
Dr. Jeang's team found evidence that the virus co-opts an enzyme produced by human cells to transport HIV's genetic material out of the cell nucleus. Once out of the nucleus, these messenger RNAs begin directing the cell to create and assemble new virus particles.
The process of how HIV genetic material--a long unedited strand of RNA--exits the cell nucleus has long puzzled scientists. Human cells cut, edit and splice RNA before it can leave the nucleus, but somehow HIV subverts that process and exports from the nucleus the long version of RNA that encodes instructions for making new viral particles.
Scientists knew that HIV makes a protein called Rev to help skirt the prohibition on transporting the lengthy, unedited version of RNA from the nucleus. They also knew that HIV commandeers a human protein known as CRM1 to aid in this process. Rev and CRM1 together, however, are insufficient to explain how HIV flouts the molecular machinery that cuts and splices RNA before it leaves the nucleus.
"Unspliced RNA is like an unwieldy ball of yarn," explains Dr. Jeang. "We found that the virus also uses a human enzyme known as DDX3 to straighten its RNA before threading it through a small pore in the nucleus." The team's experiments offer the first evidence that HIV uses DDX3 in the complex process that moves its RNA out of the nucleus. They also demonstrated that DDX3, a human RNA helicase enzyme, is essential to this process. RNA helicases are enzymes that untwist RNA molecules.
The researchers now plan to look for inhibitors, small molecules that could either lock or gum up DDX3's ability to straighten a twisted strand of RNA. Although it would take many years to develop, in the best scenario, an inhibitor for DDX3 could effectively block HIV replication. Researchers would need to find a balance between a potential inhibitor's action in shutting down viral replication and any detriment it might cause to human cells.
In the past decade, two classes of HIV inhibitor drugs, protease inhibitors and reverse transcriptase inhibitors, have greatly extended the lives of HIV-positive individuals. While these drugs target HIV enzymes, a DDX3 inhibitor would target a cellular enzyme. The researchers see a great therapeutic advantage to blocking a cellular enzyme rather than a viral enzyme.
"Unlike viral enzymes, cellular enzymes can not mutate to escape from drugs," says Dr. Jeang. The problem of drug resistance that occurs with protease and reverse transcriptase inhibitors might thus be eliminated with a successful DDX3 inhibitor.