艾滋病,蛋白质 z-bo 2020-09-19 317

　　The way to bypass the biggest obstacle to developing an AIDS vaccine may not be far away

　　The reason why HIV can defeat vaccine candidates and the body’s own line of defense is because it mutates very quickly to avoid immune responses. Ten years ago, some researchers set out to study a fundamentally different vaccine development strategy: how to "coax" the immune system to produce a rare and powerful broadly neutralizing antibody (bNAb) that can eliminate almost every HIV virus variant. Today, three different teams have taken vital steps towards this goal.

　　Many people infected with HIV will naturally produce bNAbs, but they usually appear only 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, researchers described the progress made in two different methods of stimulating the immune system to make bNAbs.

　　Although none of the methods will directly contribute to the development of AIDS vaccines, they have greatly boosted confidence: placing the correct virus fragments (immunogens) in the correct order can guide the antibody-producing B cells to secrete these all-round immunity The path of the system molecule. "We are really starting to see that reasonable vaccine design can work." Dennis Burton, an immunologist at the Scripps Research Institute in San Diego, California, said. He is also the co-author of two studies published online in the journal Science.

　　All three studies tried to reverse part of the process of B cell maturation, because in rare cases, the process will harvest cells that can produce HIV bNAb. In an article published in Science, a team led by David Nemazee and William Schief from the Scripps Research Institute described how to use a special HIV surface protein gp120 fragment to promote the maturation process. They first described this concept in the journal Science two years ago. The latest research shows that this kind of nanoparticles can indeed bind to germline B cells and enable the latter to embark on the road to mature cells that can secrete antibodies with the characteristics of bNAb.

　　Antibody is a type of Y-shaped protein. Each "arm" of Y has parts called heavy and light chains. In the HIV bNAb isolated from the infected person, a specific region of the light chain is very short. The immunogen of the nanoparticle will cause an antibody with a shortened light chain region to increase by more than 100 times. "This news is exciting." John Mascola, director of the National Institutes of Health's Vaccine Research and Development Center, said that he did not expect such a result. Schief said that his team currently wants to develop a different immunogen, hoping to give a booster injection that can trigger bNAb-like features 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 are already producing bNAb into producing more potential versions of antibodies. The particle under consideration is a complex of 3 gp120 proteins densely distributed on the surface of the HIV virus. Studying this trimer in its "natural" form is a huge challenge because it separates when it is not attached to virus particles. However, John Moore from Weill Cornell Medical College in New York already knows how to stabilize the natural-like trimer. Now, Moore, Rogier Sanders, also from Weill Cornell Medical College, and a large team of collaborators inject these natural trimers into rabbits and monkeys. As they reported in the journal Science, antibodies raised by natural trimers were effective and at least eliminated a tenacious isolate of HIV in the test tube. However, this test failed in trimers made in other laboratories.

　　The next step will be to investigate whether first injection of a different immunogen to initiate the B cell maturation process and then injection of trimer will produce a broadly applicable and effective antibody. An article published in the "Cell" magazine shows that this type of combination punch is possible. The Michel Nussenzweig laboratory of Rockefeller University in New York bred mice with genetically recombined B cells and produced antibodies that exhibit some bNAb characteristics, which is similar to what the initial immunogen might do. Through cooperation with Moore, Sanders, and Schief, Nussenzweig discovered that the trimer subsequently stimulated B cells to produce antibodies that still possess more bNAb characteristics.

　　Mascola said that eventually gp120 nanoparticles may serve as the initial "primer" injection, urging the correct germline B cells to take action. A subsequent injection of natural trimer may be given as a further reinforcement. "A successful vaccine development method will require both the correct germline signal and the administration of some sort of trimer immunogen at some point to mature the antibody." Mascola said they form two parts of a platform.

　　Also, no one knows which immunogens can direct the 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." Mascola said, "but we should value any success we have and move forward better."