Genetically engineered protein that inactivates virtually all strains of the HIV virus = Cure? Y….
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| A new drug agent could block all known strains of HIV from entering human cells, and that protection could last for decades, new research reveals. Here, HIV is seen infecting a T-cell. (Photo : Flickr / NIAID) |
Ever since HIV emerged as a deadly public health threat in the early 1980s, scientists have sought a vaccine that could repel the virus and prevent AIDS. Three decades of intensive research have come up short, although drugs to treat HIV infection have transformed the disease from a death sentence to a chronic disease people can live with.
However, in Third World countries where access to HIV drugs is limited, HIV continues to devastate populations. That could change, if a new study led by scientists from The Scripps Research Institute lives up to its promise.
The scientists have created a genetically engineered protein that inactivates virtually all strains of the virus. While it will take years before this approach can be tested in humans, the concept provides a fresh insight on how to protect people against infection from the AIDS-causing virus.
The protein mimics two receptors on the surface of the immune cells that HIV infects. When the virus encounters the protein, it springs into action as if infecting a cell. The changes the virus undergoes render it incapable of future attempts at infection, said Michael Farzan, a Scripps Research scientist who led the study.
The protein neutralized 100 percent of neutralization-resistant strains of HIV-1, HIV-2 and SHIV-AD8, an artificially made cross between HIV and simian immunodeficiency virus, an HIV relative found in monkeys. The protein was tested in cell cultures, mice with humanized immune systems and macaque monkeys given SHIV. This degree of protection far exceeds that of the strongest anti-HIV antibodies in the body's immune system.
For people, the protein could one day offer lasting protection against HIV infection by means of gene therapy, Farzan said. A designated gene would be carried into muscle cells by an innocuous virus. Then the gene, called eCD4-Ig, would be deposited into the muscle cells, where it would churn out the artificial protein into the bloodstream. If the protein encounters any HIV, it would bind to it, rendering the virus harmless.
In essence, the new study's authors said the approach acts as a vaccine against HIV.
The study was published Wednesday in the journal Nature. Farzan, in Scripps' campus in Jupiter, Florida, was the senior author. Matthew R. Gardner, also of Scripps Florida, was co-first author along with Lisa M. Kattenhorn of Harvard Medical School's New England Primate Research Center in Southborough, Mass. From Scripps' La Jolla headquarters, Dennis R. Burton, a noted expert on broadly neutralizing antibodies, also participated. More than 30 scientists in all took part in the study.
New idea
The study takes a novel approach to hitting HIV's weak spots; the receptors it must attach to infect the cells. These are called CD4 and CCR5, (along with CXCR4, a receptor close to CCR5 that can serve in its place). HIV must attach to both locations to enter into the cell, Farzan said. Once it attaches, the virus changes shape to drive itself into the cell.
If it works in people as it does in animals, the protection will be rock-solid, Farzan said.
"If we injected in a high risk individual who is not HIV positive, theyll be protected," Farzan said. "We did this very stringent HIV challenge (in animals) and we kept doubling the doses. In this paper we only went four times but now we've given 16 times the dose to infect our control animals. And these animals were completely uninfected -- zero virus. So this is better than anyone has ever shown in an animal for protection."
Scientists not involved in the study praised the study's quality, but said more extensive testing is needed to validate the concept.
"The science is very good," said Shane Crotty, a vaccine researcher at the La Jolla Institute for Allergy and Immunology. "It's quite impressive that they managed to combine the CD4 binding site and the CCR5 to really block HIV so efficiently. They're over-exuberant about the results, but it's a really nice first experiment."
Just four macaque monkeys were tested, and more monkeys need to be tested, Crotty said.
Getting permission to try the gene therapy in people presents another hurdle, Crotty said. The goal is to protect against HIV infection, so the therapy would have to be tested in healthy people. The burden of safety is higher for experimenting with healthy people than for those already sick.
Much the same views were expressed in an accompanying article in Nature. Nancy L. Haigwood of Oregon Science & Health University wrote that larger studies in non-human primates are called for.
Haigwood also wrote the intravenous method for delivering the HIV-like virus to the monkeys isn't characteristic of how most HIV is transmitted. Most HIV transmission takes place through mucus membranes, she wrote, and delivering the virus in that method would present a better model. Crotty agreed with that point.
"However, in the absence of a vaccine that can elicit broadly protective immunity and prevent infection, and given the lack of major breakthroughs on the horizon to provide one, the idea of conferring potent, sustained vaccine-like protection against HIV infection through gene therapy is certainly worth strong consideration," Haigwood concluded.
Tough road
The search for an HIV vaccine has been frustrating. None of the vaccines tested to date have effectively prevented HIV infection, although one trial showed a 32 percent reduction in HIV infections over placebo. That modest amount of protection isn't good enough.
Much vaccine research has mostly focused on finding broadly neutralizing antibodies naturally produced by HIV-positive people, and attempting to induce the immune system to make them. These antibodies attack the few unchanging areas on the HIV surface. The virus mutates rapidly, foiling most immune system attacks.
Burton, the Scripps La Jolla researcher into broadly neutralizing antibodies and study co-author, said the vaccine alternative is worth studying.
"I'm a believer in plurality until the problem's solved," Burton said. "It's an interesting approach and gets around some of the problems of vaccination. It isn't a natural molecule, so we couldn't induce it through vaccination. But it's a molecule that does better than any neutralizing antibody. It’s a good candidate to try to put into one of these genetic approaches."
Another growing area of research has focused on genetically altering immune cells so they don't produce the CCR5 receptor, hence are resistant to HIV infection. These altered immune cells are functional, indeed some people naturally lack the receptor and appear not to suffer any ill effect.
Sangamo Biosciences of Richmond, Calif, is in Phase 2 testing of a gene therapy technique that alters an HIV-infected patient's own immune cells to get rid of the receptor. The cells are modified in the lab and reinfused back into the patient. If it works, the patient's altered immune system will itself be immune to HIV infection.
The Scripps-led researchers are taking another route with the receptors. Their aim is to prevent infection in the first place, with a less drastic method than genetically modifying the immune system. Moreover, they decided to make their protein decoy resemble two receptors. The protein fuses the CD4 receptor with part of CCR5. Offering two targets should work more effectively than just one, the researchers reasoned.
Earlier research attempted to use just CD4, which has been made in a soluble form. However, the results were unpromising: limited effectiveness and at low concentrations, the molecule actually increased HIV infectivity.
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