Scientists unveil new promising HIV vaccine strategy – ScienceDaily

The new vaccination strategy described in a document of 23 November 2003 Progress of science, is based on the envelope protein of HIV, Env. This complex, changing-shaped molecule was notoriously difficult to produce in vaccines, so as to induce useful immunity against HIV.

However, scientists at Scripps Research have found a simple and elegant way to stabilize Env proteins in the desired form, even for various strains of HIV. Mounted on virus-like particles to mimic a whole virus, stabilized Env proteins elicited robust anti-HIV antibody responses in mice and rabbits. Candidate vaccines based on this strategy are now tested in monkeys.

"We view this new approach as a general solution to the long-standing problems posed by the design of an HIV vaccine," said lead investigator Jiang Zhu, badociate professor in the department of Structural Biology and Computer Science. Integrative Scripps Research.

Copies of Env study the surface of HIV; their main function is to enter the host cells and introduce them to initiate the infection. Since Env plays this crucial role in infection and is the most exposed viral structure of an infected host's immune system, it is the main target of HIV vaccination efforts. The idea was to inoculate people with the entire Env protein or subunits thereof in order to stimulate the production of antibodies binding to Env, in the hope that these antibodies will prevent HIV from infecting the animals. host cells during future exposures to the virus.

Until now, of course, no HIV vaccine has been effective in large-scale clinical trials. Many researchers believe that an HIV vaccine can work if it presents the Env proteins to the immune system in a way that looks a lot like the Env's form on a real virus before that it does not infect a cell. But presenting Env correctly was a huge challenge.

On an HIV virus, Env protrudes from the viral membrane in tight clusters of three, called trimers, and these complex structures adopt radically different forms before and after infection of cells. Researchers on HIV vaccines, despite years and tens of millions of dollars worth of experimentation, have failed to find a widely applicable method for stabilizing Env trimers in the desired form prior to infection.

"The trimer stabilization solutions that have been reported up to now have worked for some strains of HIV but could not be generalized," Zhu said. "The metastability" of commuting, as we call it, has really been a central problem for the design of a trimer – based HIV vaccine. "

Zhu, a trained biophysicist, sought a more general solution to the Env stability problem. In an article published in 2016, colleagues at Scripps Research and himself said that changing a short and slender Env section called HR1 could do the trick – it allowed Env to stay in the pre-infection, form "closed".

In the new study, he and his team showed that this strategy worked well for Env strains of various strains of HIV circulating in different parts of the world. This approach called "uncleaved optimized prefusion" (UFO), as they call it, allows to obtain stabilized Env trimers in the closed form and can be produced efficiently, with a surprisingly reduced need for purification. , in the types of cells normally used in biotechnological manufacturing.

"To date, in my lab, we have changed the data from 30 to 40 different strains of the virus to Envs, and in most cases, it worked perfectly," says Zhu.

He and his colleagues further optimized their vaccination strategy by genetically linking their stabilized Env trimers, up to 60 at a time, to individual nanoparticles mimicking the globular form of a whole virus. In this way, the vaccine molecule, although artificial and devoid of the genetic material necessary for viral replication, appears to the immune system as a true invasive virus and stimulates a stronger reaction.

In the mouse, Zhu and his team discovered that a sample of the Env-on-nanoparticles vaccine, in just eight weeks, caused the formation of antibodies that, in laboratory tests, had successfully neutralized an HIV strain. in natural circulation – of a type against which previous vaccines had generally failed.

"This is the first time that an HIV vaccine candidate induces this type of antibody response in mice," said Zhu. Similarly, unprecedented results were obtained in rabbits, demonstrating that the nanoparticle-based approach is significantly superior to the use of isolated Env proteins – it induces a much stronger response and much faster .

Other tests are currently underway at 24 monkeys at the Southwest National Primate Center, sponsored by the National Institutes of Health, in San Antonio, Texas.

Zhu and Scripps Research granted an HIV vaccine technology license to a start-up company, Ufovax LLC, which sponsors ongoing testing. "We are currently testing two candidate trimer-based vaccines of different strains of HIV, as well as a third candidate vaccine that consists of a badtail of three Env-based vaccines," said Ji Li, director General of Ufovax. "We believe this new approach represents a breakthrough after 30 years of research on an HIV vaccine."