Scientists from The Scripps Research Institute (TSRI) have presented a paper in the journal Nature, titled AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges, which outlines a novel approach to treating the HIV virus that causes AIDS.
The new approach has protected four laboratory monkeys over a year-long period from repeated exposure to an HIV variant used in lab tests called SHIV.
How does it work? The new treatment tricks the HIV virus into beginning viral replication with a custom decoy protein that is designed to mimic CD4 lymphocytes (a type of white blood cell, commonly called T cells) that are produced by the immune system to fight infections.
What normally happens in HIV viral replication is the virus attaches to a receptor on the surface of the CD4 cell, this in turn exposes a second receptor, the CCR5 receptor. Once the HIV virus successfully attaches itself to both the CD4 and CCR4 receptors it undergoes a shape change that allows it to inject its RNA into the cell.
Once its RNA is injected into the white blood cell, the cell essentially becomes a factory for rapidly reproducing more and more HIV virus. If not controlled, the viral replication leads to progressive destruction of the immune system that eventually results in Acquired Immune Deficiency or AIDS.
Interrupting this HIV replication has proven difficult. Part of the problem is that there are not one but three major strains of HIV: the main family, known as HIV-1, which is responsible for the majority human cases of the disease; HIV-2 and finally SIV (Simian Immunodeficiency Virus) which affects monkeys.
In turn, each of these different strains have their individual variations caused by genetic mutations. Because the HIV virus mutates rapidly, small mutations in the receptor sites have made it difficult to make a vaccine or find a universal antiviral treatment that addresses all the HIV strains and corresponding genetic variations.
That’s one of the reasons that the monkey study conducted by scientists at The Scripps Research Institute, along with researchers from Harvard, Princeton, Rockefeller University, the University of Southern California and the Pasteur Institute in France is a potential breakthrough. Their novel approach of using a decoy protein, seems to be potentially effective against all different HIV strains.
“Our compound is the broadest and most potent entry inhibitor described so far,” said TSRI Professor Michael Farzan, who led the research effort. “Unlike antibodies, which fail to neutralize a large fraction of HIV-1 strains, our protein has been effective against all strains tested, raising the possibility it could offer an effective HIV vaccine alternative.”
The decoy protein binds to two locations on the HIV virus at the same time. This triggers the HIV virus to begin replication, but unlike normal cells the unique Y shape of the decoy protein doesn’t allow the HIV virus sufficient contact area to do any damage.
Unlike normal HIV treatments, “when antibodies try to mimic the receptor, they touch a lot of other parts of the viral envelope that HIV can change with ease,” said TSRI Research Associate Matthew Gardner, the first author of the study along with Lisa M. Kattenhorn of Harvard Medical School. “We’ve developed a direct mimic of the receptors without providing many avenues that the virus can use to escape, so we catch every virus thus far.”
“This is the culmination of more than a decade’s worth of work on the biochemistry of how HIV enters cells,” Farzan said. “When we did our original work on CCR5, people thought it was interesting, but no one saw the therapeutic potential. That potential is starting to be realized.”
The next step in evaluating this approach is to test whether the decoy protein can stop the virus from replicating in monkeys already infected with SHIV. If successful, it would represent a therapeutic treatment of HIV in the animal model.
If that proves successful, Dr. Anthony S. Fauci, Director of the National Institute of Allergy and Infectious Diseases says the testing will move from the animal model to testing in humans.