The current strategy against HIV symptoms is the use of drug cocktails that mainly target three enzymes produced by the virus. However, the periodically popping up resistant strains can thwart the drug combos.
Researchers at the University of California, Berkeley, and the National Institutes of Health have identified a fourth protein, Nef or negative factor. This protein hijacks host proteins. The researchers have captured a high-resolution snapshot of Nef bound with a main host protein, and discovered a portion of the host protein that will make a promising target for the next-generation of anti-HIV drugs. It could be possible to slow or stop HIV by blocking the part of a key host protein to which Nef binds.
The report comes a month after President Barack Obama pledged to redirect $100 million in the NIH budget to accelerate development of a cure for AIDS, though therapies to halt the symptoms of AIDS will remain necessary for the immediate future, Bonifacino said.
"We have imaged the molecular details for the first time," said structural biologist James H. Hurley, UC Berkeley professor of molecular and cell biology. "Having these details in hand puts us in striking distance of designing drugs to block the binding site and, in doing so, block HIV infectivity." The findings are reported in online journal eLife.
"For many patients, current drug therapies have transformed HIV infection into a chronic condition that doesn't lead to AIDS, but anything we can develop to further interfere with replication and propagation of the virus would help keep it in check until we find a way to completely eliminate the virus from the body," Hurley said.
There are a small number of genes within HIV that produce just about 15 proteins but each of them hijack some aspect of immune cells' internal machinery producing more copies of the virus.
The anti-AIDS drugs currently available block three HIV enzymes. These are proteins that transcribe and insert virus' genetic material and snip some encoded proteins. Researchers are now looking for drugs to target the other proteins and thereby support current therapies. In other words, they are searching for ways to block sites on host proteins to which the virus proteins bind in order to stop HIV. This has to be done without interfering with normal cell function, however.
Over two decades ago, scientists discovered that HIV is far less infective in the absence of the protein Nef. With a Nef-defective virus, patients can live for decades without complications. More details about Nef have been coming in over the years. HIV enters immune system cells via a receptor called CD4, but once "HIV gets into cells through the CD4 door, it slams the door shut behind itself to prevent unproductive re-infection," Hurley said. Scientists do not know why HIV slams door on other viruses. This could possibly be strategy to make viral replication more effective.
The virus prevents further HIV infection by ridding the cell surface of all other CD4 receptors. Nef achieves this by tagging the CD4 receptor so that the cell thinks it is trash and carries it to the cell's incinerator, the lysosome, where it is destroyed. This was observed by Bonifacino and colleagues six years ago, when they found that Nef does this by directly binding to a host protein, AP2, that latches onto a protein called clathrin. This causes the cell membrane to bulge inward and pinch off to form a small membrane bubble that carries attached CD4 receptors to the lysosome for destruction.
"The new high-resolution image reveals a cavity at the site where Nef binds to AP2, that could be a good site for drug targeting," Bonifacino said.
"This cavity on AP2 is not known to be used by any other host protein, so if we interfere with the cavity we are not going to interfere with any host cell function, only the function of Nef," he said. "This will inform better searches for inhibitors."
Hurley cautioned, however, that the research "needs more validation to prove that the cavity is a target. But we are excited because it is a potential target, and these things don't come along every day."
"This work was an extension of our work on clathrin adaptors, an opportunity to do something relevant to fighting HIV that was based on the purely basic research we are doing on the sorting of proteins to lysosomes," Hurley said.
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