Study Suggests Alternative Approach to AIDS Vaccine

Decoy protein

Caption: A decoy protein that mimics the CD4 receptor (red), the CCR5 receptor (green), and a natural antibody (grey), binds to the HIV envelope protein (three white blobs) and blocks it from infecting immune cells.
Credit: Michael Farzan

Over more than a century, researchers have succeeded in developing vaccines to prevent polio, smallpox, cervical cancer, and many other viral diseases. For three decades now, they have tried to design an effective vaccine for the human immunodeficiency virus (HIV) that causes AIDS. Despite plenty of hard work, lots of great science, and some promising advances along the way, an effective traditional vaccine still remains elusive. That has encouraged consideration of alternative approaches to block HIV infection.

Now in the journal Nature [1], an NIH-funded team reports promising early results with one of these interesting alternatives. The team hypothesized that producing a protein that binds to HIV and prevents it from entering cells might provide protection. So they designed such a protein, and, using an animal model, introduced multiple copies of a gene that makes this protein. In a small study of non-human primates, this gene-therapy approach blocked HIV infection, even when the animals were exposed repeatedly to large doses of the virus.

Traditional vaccines work by acquainting the immune system with a non-infectious piece of a virus or a deactivated version of the entire thing. This forced introduction primes our immune systems to recognize live virus later, should an infection ever occur, and to knock out the invaders with proteins called antibodies.

But HIV has turned out to be a diabolical moving target that mutates constantly and subtly changes the shape of its coat proteins. Our immune cells, though primed to produce antibodies that will take out HIV, can’t eliminate a target that keeps changing its shape. Likewise, traditional vaccine makers haven’t been able to stay ahead of all of HIV’s many spontaneous disguises to neutralize it broadly, and some of the virus continues to slip past our immune cells undetected, loop back around, and infect them.

This lack of success with traditional vaccines has caused some researchers to take a harder look at how HIV infects immune cells, instead of trying to prevent the virus from reaching them. The process has focused on a special structure on the surface of HIV called the envelope protein, which docks on our immune cells via a receptor protein called CD4. After anchoring to CD4, the envelope protein changes shape, exposing a previously hidden region that now binds to a second protein receptor on the immune cell called CCR5. Once bound to both receptors, HIV injects its own genetic material, creates copies of itself, and eventually kills the cell.

Michael Farzan, a researcher at The Scripps Research Institute in Jupiter, Florida and senior author on the Nature study, decided two targets are better than one. He and his colleagues engineered a synthetic decoy protein that mimicked both of the receptors to which HIV likes to dock. At one end of the Y-shaped molecule they inserted a tiny piece of the CD4 receptor protein. On the opposite end was segment of the CCR5 protein. In between these two regions was a linker normally used by an antibody. Farzan speculated that this synthetic protein would neutralize HIV by attaching to the two locations on the envelope protein that bind to the immune cell’s CD4 and CCR5. The antibody part of the protein would then alert the immune system, which would then destroy the HIV tagged with the synthetic protein.

Farzan first tested the synthetic protein called eCD4-Ig in the test tube. He found that it was more effective at blocking multiple strains of HIV from infecting immune cells than the natural antibodies present in people who are immune to the virus. His team also found that mice vaccinated with eCD4-Ig protein were protected from HIV.

To test the protein in macaques, Farzan and his colleagues engineered a gene to produce eCD4-Ig, placed the gene into a harmless virus, and then injected the construct into the muscles of four animals. The virus infected the muscle cells and transformed them into factories that cranked out large quantities of the synthetic protein. The macaques were then challenged with increasing doses of SHIV (a hybrid virus made from the simian immunodeficiency virus (SIV) and HIV genomes) over 34 weeks. All four vaccinated animals were protected, while all of the controls were infected.

As promising as these results are, the study was small and must be replicated in larger animal studies before even considering a human clinical trial.

Farzan’s approach is built on a similar strategy that was first tried in 2009 [2]. That work, led by Philip Johnson of the Children’s Hospital of Philadelphia, used gene therapy to introduce a gene for a designer antibody that conferred protection against SIV, a cousin of HIV. Other NIH-funded teams are using this alternative gene-therapy vaccination strategy to bypass the immune system to generate potent inhibitors that can block HIV infection entirely. Several of these are already in human clinical trials, and Farzan, too, hopes to get there within the next year.

References:

[1] AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Gardner MR, Kattenhorn LM, Farzan M, et al. Nature. 2015 doi:1038

[2] Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys. Johnson PR, Schnepp BC, Zhang J, Connell MJ, Greene SM, Yuste E, Desrosiers RC, Clark KR. Nat Med. 2009 Aug;15(8):901-6.

Links:

HIV/AIDS Fact Sheet (World Health Organization)

HIV Vaccine Research (National Institute of Allergy and Infectious Diseases/NIH)

Michael Farzan  (The Scripps Research Institute, Jupiter, FL)

NIH Support: National Institute of Allergy and Infectious Diseases; National Center for Research Resources, and National Center for Advancing Translational Sciences.