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The search for an HIV vaccine has been in the hands of scientists for many years, and despite some advances in the field, most of the failures have been in researchers' journeys. A new vaccination method based on the structural modification of the viral protein ca. has been successfully tested in mice and could represent one of the first real advances in the fight against HIV in the last 30 years.
The new vaccination strategy, described in an article published in the journals Science Advances, is based on the HIV envelope protein, called ca.. This complex molecule, with its variable form, was particularly difficult to synthesize in vaccines, so as to induce an effective immunity against HIV.
However, scientists from Scripps Research have found a simple and elegant method to stabilize proteins ca. in the desired form, including for various strains of HIV.
Mounted on particles resembling viruses, to mimic a real virus, proteins ca. stabilized antibodies provoked 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 challenges of designing an HIV vaccine Says Jiang Zhu, badociate professor in the department of structural biology and integrative informatics Scripps Research.
Target viral surface protein ca.
Sinceca. plays a 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 protein ca. whole or subunits thereof in order to stimulate the production of antibodies binding to ca.in the hope that they will prevent HIV from infecting host cells in future exposures to the virus.
Viral envelope protein ca. (gp120 and gp41) is crucial in the process of infection of the host cell. It allows HIV to pair and initiate its insertion into the cell, so it is a direct target for a vaccine. Credits: Patrice Boucher
Many researchers believe that an HIV vaccine can work if it has the proteins ca. to the immune system in a way that looks a lot like the shape of theca. on a real virus before it infects a cell. But correctly presenting this protein has been a huge challenge.
On the same topic: First promising results for human clinical trials of an HIV vaccine
On HIV, ca. is present on the tightly clustered viral membrane of three structures, called trimers, and these complex structures adopt radically different forms before and after infection of cells. Researchers, despite years and tens of millions of dollars of experimentation, have never managed to find an effective method to stabilize trimers ofca. in the desired form before infection.
" The trimer stabilization solutions that have been reported so far have worked for some HIV strains, but could not be generalized Zhu explains. " The metastability of Env has really been a central issue for the design of a trimer-based HIV vaccine ".
A strategy based on the structural modification ofca.
Zhu, a trained biophysicist, sought a more general solution to Env's stability problem. In an article published in 2016, his colleagues from Scripps Research and he himself suggested that the modification of a short and linear section ofenv, called HR1, could do the trick.
In the new study, researchers have shown that this strategy is proving effective for trimers ofca. from various strains of HIV circulating in different parts of the world. This so-called "optimized non-cleaved prefusion" (UFO) approach makes it possible to obtain trimers ofca. stabilized in the closed form, and can be efficiently produced with a surprisingly reduced need for purification, in the types of cells normally used in biotechnological manufacturing.
This illustration shows, on the left, a modified Env trimer (in yellow) bound by neutralizing antibodies. On the right, several modified trimers (in yellow) integrated into a nanoparticle (blue) to mimic a whole virus. Credits: Jiang Zhu / Scripps Research
Zhu and colleagues have further optimized their vaccination strategy by genetically linking their trimersca. stabilized, 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 just eight weeks in the mouse, Zhu and his team discovered that a vaccine sample ca.-on-nanoparticles had caused the appearance of antibodies that, in laboratory tests, had neutralized a naturally circulating strain of HIV – of a type against which previous candidate vaccines had generally failed.
" This is the first time that an HIV vaccine candidate induces this type of antibody response in mice Zhu says. Similarly, unprecedented results have been obtained in rabbits, demonstrating that the nanoparticle-based approach is clearly superior to the use of proteins. ca. isolated; it induces a much stronger response, and much more quickly.
Other tests are currently underway in 24 monkeys at Southwest National Primate Center, under the authority of National Institutes of Health.
" We are currently testing two vaccine candidates based on Env trimers of different HIV strains, as well as a third candidate vaccine consisting of a badtail of three Env-based vaccines. We believe this new approach represents a breakthrough after 30 years of research on an HIV vaccine Concludes Ji Li, director of Ufovax LLC, the biotechnology laboratory currently testing.
Sources: Science Advances
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