HIV travels lightly. The virus' genome contains genes for only 15 proteins, but that means it is all the more dependent on the proteins of the cells it infects to propagate.
In a paper published in the Jan. 10, 2008, issue of SciencExpress, researchers from Harvard Medical School published a study surveying such host cell proteins.
While that list probably still is not comprehensive, it nevertheless quadruples the list of known cellular HIV accomplices, and provides a wealth of potential drug targets.
The researchers said that targeting host factors rather than viral ones could have advantages.
"Such proteins represent therapeutic targets that are not plagued by the twin problems of viral diversity and escape mutation that interfere with the effectiveness of conventional anti-retroviral drugs," they wrote in their paper. "We anticipate that HIV would be hard-pressed to evolve resistance to drugs targeting cellular proteins, because it would have to evolve a new capability, not simply mutate a drug-binding site."
First author Abraham Brass acknowledged that targeting host factors has obvious disadvantages as well. Drugs targeting the host are almost sure to have more side effects than those targeting the virus.
But, Brass told Bioworld Today, "Most of the medicines we deliver are to host factors." And that includes those that are critical for cell function. While Brass said that it would be preferable, given the choice, to target a protein that's more important to HIV than to the host cell, in current medical practice "there's quite a few essential proteins that we medicate."
In cell culture experiments the authors used short interfering RNAs to first knock down a single gene, and then exposed the cells to HIV. They found 273 siRNAs that led to reduced HIV replication, meaning the protein those siRNAs affect are required for the virus to grow. The researchers found such stalwarts as the HIV receptor CD4 and co-receptor CXCR4, showing that the method indeed can uncover host proteins that are important for HIV replication; but of the 273 proteins, nearly 90 percent were not previously known to be important for HIV's ability to thrive within its host.
The proteins identified by the screen are involved in a variety of cellular functions. The scientists highlighted the HIV's dependence on autophagy, a cellular inventory control mechanism, as an "unexpected" association.
Following the initial screen, the researchers selected three proteins from different parts of HIV's life cycle for further characterization. Rab6 and Vps53 are involved with retrograde transport from the Golgi network to the endoplasmic reticulum, and transportin3 imports proteins into the cell nucleus.
They found that while Rab6 depletion reduced HIV infection, it did not affect CD4 or CXCR4, which are recycled by retrograde transport. Rab6 depletion also protected cells from infection with viral strains that do not use CXCR4 as a co-receptor, meaning that HIV's dependence on Rab6 probably is due to something other than Rab6's effect on receptor transport - though the researchers did point out that their screen also identified more than 30 transmembrane proteins that were not previously linked to HIV, opening up the possibility of an as-yet unidentified co-receptor.
The team also showed that silencing transportin 3 somehow prevents HIV from integrating into the host genome. In their paper, the scientists said that whether transportin interacts with the virus directly or indirectly, via altered import or splicing of an HIV-dependency factor that is necessary for the virus to integrate, "remains to be determined."
But first author Abraham Brass told BioWorld Today that he personally is most interested in transportin 3, because he believes it may be interacting directly with the virus. "Rab6 works indirectly - I don't believe that it's touching the virus at all," he said. "Transportin 3's effects might be direct" - a theory that he currently is testing.