Back HIV Treatment Search for a Cure Novel Entry Inhibitor May Provide Vaccine-like Protection Against HIV

Novel Entry Inhibitor May Provide Vaccine-like Protection Against HIV

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A potential new therapy using a molecule that mimics both the CD4 receptor and the CCR5 co-receptor can stop an HIV-like virus from entering host cells, researchers reported in the February 18 online edition of Nature. Monkeys given gene therapy to produce the eCD4-Ig protein did not become infected after repeated virus exposures, suggesting it may be an effective HIV vaccine alternative as well as a long-acting therapy.

HIV infects T-cells by attaching its gp120 envelope protein to the cell's CD4 receptors. Most strains of the virus also require the CCR5 co-receptor (though some strains use an alternate co-receptor, CXCR4). Once HIV has attached to both receptors, it can enter the cell, insert its genetic material into the cell's nucleus, and begin producing new virus.

Michael Frazan from Scripps Research Institute and colleagues created an antibody-like protein, dubbed eCD4-Ig, with sections that mimic both CD4 and CCR5. When HIV attaches itself to this decoy molecule, it becomes unable to infect host cells. In laboratory studies eCD4-Ig neutralized 100% of a panel of diverse HIV-1, HIV-2, and simian immunodeficiency virus (SIV) strains that infect monkeys, including some that were resistant to CD4 blockage alone.

Using gene therapy delivered via an adeno-associated virus (AAV) vector to rhesus macaques, the researchers were able to make monkey muscle cells produce eCD4-Ig for more than 40 weeks. All 4 monkeys that received the therapy were protected from infection when exposed multiple times to large amounts of an HIV/SIV hybrid virus, while all untreated animals became infected.

Although it does not stimulate natural immunity like traditional vaccines, the new therapy is more potent than the best known broadly neutralizing antibodies. "Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine," the researchers concluded.

"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," National Institute of Allergy and Infectious Diseases director Anthony Fauci stated in a National Institutes of Health press release. NIAID has funded this ongoing research through an initiative called Beyond HAART: Innovative Therapies to Control HIV-1.

Below is an edited excerpt from a Scripps press release describing the study findings in more detail.

Scripps Florida Scientists Announce Anti-HIV Agent So Powerful It Can Work in a Vaccine

Jupiter, FL -- February 18, 2015 -- In a remarkable new advance against the virus that causes AIDS, scientists from The Scripps Research Institute (TSRI) have announced the creation of a novel drug candidate that is so potent and universally effective, it might work as part of an unconventional vaccine.

The research, which involved scientists from more than a dozen research institutions, was published February 18 online ahead of print by the prestigious journal Nature.

The study shows that the new drug candidate blocks every strain of HIV-1, HIV-2 and SIV (simian immunodeficiency virus) that has been isolated from humans or rhesus macaques, including the hardest-to-stop variants. It also protects against much-higher doses of virus than occur in most human transmission and does so for at least eight months after injection.

"Our compound is the broadest and most potent entry inhibitor described so far," said Michael Farzan, a professor on TSRI's Florida campus who led the 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."

Blocking a Second Site

When HIV infects a cell, it targets the CD4 lymphocyte, an integral part of the body’s immune system. HIV fuses with the cell and inserts its own genetic material -- in this case, single-stranded RNA -- and transforms the host cell into a HIV manufacturing site.

The new study builds on previous discoveries by the Farzan laboratory, which show that a co-receptor called CCR5 contains unusual modifications in its critical HIV-binding region, and that proteins based on this region can be used to prevent infection.

With this knowledge, Farzan and his team developed the new drug candidate so that it binds to two sites on the surface of the virus simultaneously, preventing entry of HIV into the host cell. "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 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."

The team also leveraged preexisting technology in designing a delivery vehicle -- an engineered adeno-associated virus, a small, relatively innocuous virus that causes no disease. Once injected into muscle tissue, like HIV itself, the vehicle turns those cells into "factories" that could produce enough of the new protective protein to last for years, perhaps decades, Farzan said.

Data from the new study showed the drug candidate binds to the envelope of HIV-1 more potently than the best broadly neutralizing antibodies against the virus. Also, when macaque models were inoculated with the drug candidate, they were protected from multiple challenges by SIV.

"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."

2/20/15

Reference

MR Gardner, LM Kattenhorn, HR Kondur, Michael Farzan, et al. AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature. February 18, 2015 (Epub ahead of print).

Other Sources

Scripps Research Institute. Scripps Florida Scientists Announce Anti-HIV Agent So Powerful It Can Work in a Vaccine. Press release. February 18, 2015.

National Institutes of Health. NIH-Funded Scientists Create Potential Long-Acting HIV Therapeutic. Press release. February 19, 2015.