NIH-Funded Scientists Create Potential Long-Acting HIV Therapeutic
New Molecule also Might Prevent HIV Infection
Scientists have created a new molecule that shows promise for controlling HIV without daily antiretroviral drugs. 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 authors note that the molecule potentially could be used as both a preventative drug and as a treatment. The new findings appear in the February 18 issue of the journal Nature.
"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," said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.
The research was led by Michael Farzan, Ph.D., a professor in the department of infectious diseases at The Scripps Research Institute in Jupiter, Florida. The work was funded primarily by NIAID.
The new molecule is called eCD4-Ig and works by tightly binding to two unchanging sites on the surface of HIV that the virus uses to attach to receptors on cells called CD4 and CCR5. Typically, when HIV attaches to these receptors, it unlocks a door to the cell and gets inside. However, when eCD4-Ig binds to HIV, it effectively takes away the virus’s key, locking it out of the cell and preventing it from multiplying.
To make eCD4-Ig, the scientists took an antibody-like molecule that latches onto the CD4 binding site but does not neutralize HIV on its own, and fused it with a short protein fragment that attaches tightly to the CCR5 binding site. Together, these two arms of the molecule are much more effective at stopping HIV than either one is alone.
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 for the entire 40-week study period.
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. Scientists have been investigating these antibodies as another promising approach to long-acting treatment for HIV.
"Our molecule appears to be the most potent and broadest inhibitor of HIV entry so far described in a preclinical study," said Dr. Farzan. "If one could inject either eCD4-Ig or our gene therapy tool into people with HIV infection, it might control HIV for extended periods in the absence of antiretroviral drugs. Further research will help illuminate the promise of these approaches."
To build on their findings, the scientists are studying both the therapeutic potential of eCD4-Ig in monkeys infected with HIV-like viruses and the ability of eCD4-Ig to prevent infection against a wider range of HIV and HIV-like strains.
NIAID has funded the newly published and ongoing research through an initiative called Beyond HAART: Innovative Therapies to Control HIV-1, which supports the development of strategies for suppressing HIV in the absence of antiretroviral drugs. Dr. Farzan’s principal partners in this endeavor are Ronald C. Desrosiers, Ph.D., of the University of Miami Miller School of Medicine; Guangping Gao, Ph.D., of the University of Massachusetts Medical School; and Tajib A. Mirzabekov, Ph.D., of Biomirex Inc.
This research was supported by NIAID grants numbers R01 AI091476, R01 AI080324, P01 AI100263, and R01 AI058715. It was also supported by grant number P51 RR000168 from the National Center for Research Resources at NIH.
MR Gardner et al. AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature DOI: 10.1038/nature14264 (2015).