A two-armed molecule has been developed that effectively locks HIV in a kind of miniature full nelson, preventing the virus from wrestling its way into the body’s immune cells. Even better, the molecule is something the body’s own cells can be taught to produce, so that it may keep grappling with HIV indefinitely.
The molecule, called eCD4-Ig, has an arm that latches onto HIV’s CD4 binding site and an arm that attaches to HIV’s CCR5 binding site. The ambidextrous eCD4-Ig was created by researchers based at The Scripps Research Institute. They fused an antibody-like molecule that can seize the CD4 binding site, but cannot neutralize HIV on its own, with a short protein fragment that grasps the CC5 binding site. Together, these two arms of the molecule are much more effective at stopping HIV than either one is alone.
The molecule foils a wider range of HIV strains in the laboratory than any known broadly neutralizing HIV antibody and is more powerful than some of the most potent of these antibodies. In addition, the molecule safely protected monkeys from infection with an HIV-like virus during a 40-week study period. Together, the data suggest that the molecule could, with further research, be used to subdue HIV in humans.
The Scripps researchers, who were led by Michael Farzan, Ph.D., say that the molecule potentially could be used as both a preventative drug and as a treatment. It could avoid the need for daily antiretroviral drugs and even circumvent the need for a conventional vaccine for HIV.
“Our compound is the broadest and most potent entry inhibitor described so far,” said Dr. Farzan. “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.”
To test whether eCD4-Ig would protect monkeys from an HIV-like virus (simian immunodeficiency virus, or SIV), the scientists synthesized genetic instructions for making the molecule and placed them inside a harmless carrier virus called adeno-associated virus, or AAV. This gene-therapy tool was designed such that once the AAV-modified virus infected a cell, it would cause the cell to make eCD4-Ig indefinitely.
The researchers injected the genetically modified AAV into four monkeys. Then they exposed both the treated monkeys and four untreated monkeys to SIV six times at increasingly higher doses over a 34-week period. None of the treated monkeys became infected with SIV, while all of the untreated monkeys did. The eCD4-Ig molecule made in the monkey's cells persisted in the animals' blood in a fully functional form and at protective concentrations.
The new findings appeared February 18 in the journal Nature, in an article entitled, “AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges.” The article indicated that eCD4-Ig’s success in thwarting HIV is likely due to the molecule’s ability to take hold of conserved regions of HIV-1’s envelope glycoprotein (Env).
“Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any [broadly neutralizing antibody, or bNAb],” wrote the authors. “For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2, and simian immunodeficiency virus isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46, and 3BNC117.”
In addition, the scientists found that while monkeys' immune systems view both eCD4-Ig and broadly neutralizing antibodies to HIV-like viruses as foreign molecules to some degree, the undesirable immune response generated by eCD4-Ig is milder than that generated by infusions of broadly neutralizing HIV antibodies.
“Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine,” concluded the authors of the Nature article. Following up on this point, Dr. Farzan pointed out that “if one could inject either eCD4-Ig or our gene therapy tool into people with HIV infection, it might control HIV for extended periods.”
“This innovative research holds promise for moving us toward two important goals: achieving long-term protection from HIV infection, and putting HIV into sustained remission in chronically infected people,” commented Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.