Design proteins to fight AIDS

It may not be a long way to get around the biggest obstacle to developing an AIDS vaccine The reason why HIV can defeat the candidate vaccine and the body's own defense line is that it mutates very quickly, thus avoiding the immune response Ten years ago, some researchers began to study a fundamentally different vaccine development strategy: how to "trick" the immune system into producing a rare and powerful class of broad neutralizing antibodies (bNAb), which can eliminate almost every variant of HIV Today, three different groups have made crucial strides towards this goal Many people infected with HIV naturally produce bNAb, but they usually do not appear until a few years after the initial infection This means that they have little effect in helping to suppress the virus However, some experiments in monkeys have confirmed that injecting bNAb into uninfected monkeys can prevent them from contracting HIV Recently, in two articles published online in science and one in cell, the researchers described the progress made in two different ways to stimulate the immune system to make bNAb Although there is no way to directly promote the development of AIDS vaccines, they have greatly increased confidence that the correct viral fragments (immunogens) are arranged in the right order, which can guide the antibody producing B cells to the path of secreting these totipotent immune system molecules "We're really beginning to see that rational vaccine design can work." According to Dennis Burton, an immunologist at the Scripps Institute in San Diego, California He is also co-author of two studies published online in the journal Science All three studies attempted to reverse part of the B-cell maturation process, which in rare cases results in the production of HIV bNAb producing cells In an article published in science, a team led by David nemazee and William schief from the Scripps Institute described how to use specially designed HIV surface protein gp120 fragments to promote the maturation process They first described the idea in science two years ago The latest research shows that the nanoparticles can indeed bind to the germline B cells and enable the latter to secrete mature cells with antibodies indicating bNAb characteristics The antibody is a Y-shaped protein that has parts called heavy and light chains on each "arm" of Y A specific region of the light chain is very short in the HIV bNAb isolated from the infected The immunogen of nanoparticles can lead to more than 100 times increase of antibody with shortened light chain area "The news is exciting." John mascola, director of the National Institutes of health vaccine research and development center, said he did not expect this result Schief said his team currently wanted to develop a different immunogen that, after a single dose of booster injection, could trigger features like bNAb in the heavy chain The results of the other two articles show that another HIV protein complex may be able to "trick" B cells that have been making bNAb to produce more potential versions of the antibody The particle under consideration is a complex of three gp120 proteins that are densely distributed on the surface of HIV Studying the trimer in its "natural" form is a huge challenge because it separates when it is not attached to a virus particle However, John Moore, from the medical school of will Cornell in New York, has learned how to stabilize trimers in natural forms Now Moore, rogier Sanders, also from the medical school of will Cornell, and a large team of collaborators inject these natural trimers into rabbits and monkeys As they report in the journal Science, antibodies triggered by natural trimers are effective, and at least kill a stubborn isolate of HIV in a test tube However, the test failed in other laboratory made trimers The next step will be to investigate whether injecting a different immunogen to start the B cell maturation process and then the trimer will produce a broad and effective antibody According to an article published in the journal Cell, this kind of combo is possible In the lab of Michel nussenzweig at Rockefeller University in New York, mice with B-cell gene recombination were bred to produce antibodies that show some bNAb characteristics, similar to what the initial immunogen might do In collaboration with Moore, sanders and schief, nussenzweig found that the trimer then stimulated B cells to produce antibodies that still had more bNAb characteristics Eventually, the gp120 nanoparticles could act as an initial "attractor" injection, pushing the right germline B cells to act, mascola said Subsequently, a dose of natural trimer may be injected as further reinforcement "A successful vaccine development approach will require both correct germline signals and at some point the maturation of antibodies by giving some kinds of trimer immunogens." They form two parts of a platform, says mascola What's more, no one knows which immunogens can guide B cells that produce bNAb to complete these difficult steps "You have to face the reality: there is no shortcut to developing an AIDS vaccine." "But we should value any success and move forward better," said mascola