动物造模,HIV疫苗 z-bio 2021-11-26 400

　　The development of effective neutralizing antibody-based HIV-1 vaccines involves the homogenization of multiple immunoglobulin receptors that express the specificity of one or more classical broadly neutralizing antibody (bNAb) epitope clusters Recognition, usually considered to require activation. The maturation of antibody affinity is achieved through effective antigen-driven selection. Facts have proved that how to achieve this feat through vaccination is a daunting scientific challenge. One obstacle to the rational design of HIV-1 vaccines is the molecular, biological and immunological reasons for the universal induction of bNAb, which leads to this type of immune response and lacks non-relative primate models.

　　 Given that most of the HIV-1bNAbs discovered so far are from humans who have been infected with HIV-1 for a long time, researchers at the University of Pennsylvania and Duke University’s Perelman School of Medicine are all primates. . One way to induce the production of this antibody is to use a simian-human immunodeficiency virus (SHIV) strain, which carries the main HIV-1 envelope protein (Env), including those that induce bNAb in the human body, and is used to infect humans. River monkey.

　　 Rhesus monkeys infected with SIV can be used to evaluate the potential of specific HIV-1 Envs to induce bNAb and explain the common evolutionary pathway of bNAb strains and their homologous Env intermediates. This provides molecular guidance for rational vaccine design. The latest innovation in SIV design allows us to test this experimental strategy. In naturally infected humans, the neutralizing antibodies caused by HIV-1 and Env viruses co-evolve in a unique molecular model, resulting in a significant degree of neutralization in some cases. These researchers produced bNAbs from three people infected with HIV-1. They constructed SIVs with the main communicator/founder Env, and infected 22 rhesus monkeys with these SIVs. The bNAb produced by 7 rhesus monkeys has neutralizing effect and potency. Unexpectedly, SIV infection caused a molecular pattern of co-evolution of Env antibodies in rhesus monkeys. This molecular pattern reflects the situation found in people infected with the HIV-1 virus, which in some cases carries a homologous Env. The similarities include conservative immune genetic, structural and chemical solutions for epitope recognition, as well as precise substitutions, insertions and deletions of Env amino acids that maintain the virus. Rhesus monkey antibodies can neutralize 49% of the 208 virus strains in the world. It contains a 24 amino acid heavy chain complementarity determining region 3 (HCDR3) with sulfated tyrosine on top. The rhesus bNAb antibody has a V2 vertex recognition pattern similar to human bNAbPGT145 and PCT64-35S, and the important interaction with EnV includes lysine or arginine at positions 121, 166 and 169 of Env and N at position 160. -Linked glycans. Another rhesus monkey antibody binds to CD4 by mimicking the CD4 binding sites of human bNAb8ANC131, CH235, VRC01. In other rhesus monkeys infected with SHIV, the bNAb response targets the typical V3 high mannose patch epitope cluster containing Env residues 324 GDIR327 and N332. Rhesus monkeys infected with SIV and humans infected with HIV-1 have similar molecular patterns of epitope evolution, which can allow the virus to escape and promote the maturation of bNAb affinity. In addition to naturally infected humans, rhesus monkeys infected with SIV are the only model system that can co-evolve immunogens (Env) and neutralizing antibodies. The high variability and dynamic replication of HIV-1 and SHIV in vivo lead to the continuous evolution of virus quasispecies, which have sufficient binding affinity to promote the maturation of bNAb lineage affinity, which means that Env is continuously produced. Therefore, rhesus monkeys infected with SIV guide the evolution of precursor B cells in the affinity maturation stage, thereby identifying Env intermediates that can achieve significant neutralization and effectiveness, and have a new understanding of vaccine design.