Chinese and American scientists co-discovered HIV broadly neutralizing antibodies and the mechanism of their mature process
Source：Yiming Shao
2016-05-24
How to elicit neutralizing antibody especially broadly neutralizing antibody (bNAbs) which could neutralize the prevalent pandemic strains has always been a hot issue in the field of AIDS research and is the key for the success of HIV vaccine. In recent years, VRC01 was directed against the region of CD4 binding site (CD4bs) on HIV-1 gp120 was isolated and a series of bNAbs which could neutralize 80~90% of HIV-1 pandemic strains had been identified. These bNAbs mostly came from African or Caucasian patients which had been infected with HIV for a long time (5-10 years). The occurrence frequency of bNAbs was low in HIV infected donor (~5%). Most isolated bNAbs had been matured completely with higher somatic hypermutation (SHM) (20-30%). These features of bNAbs became main obstacles to the development of HIV vaccine, because currently available vaccines could not effectively induce protective antibody in immunized population for a limited time.
In cooperation with the scientists at the Scripps Research Institute, Dr. Yiming Shao group at the Chinese Center for Disease Control and Prevention had systematically researched bNAbs within an HIV-1-infected Chinese donor. A CD4 binding site directed at antibody-DRVIA7 was isolated using single B cell sorting and monoclonal antibody expression technology. Dynamic antibody evolution was revealed by unbiased analysis of B cell repertoires. This study captured the process of this lineage antibody from birth to mature. Gene sequence analysis revealed that the heavy chain of DRVIA7 was IgHV1-02*02 allelic origin with a SHM of 19% which was lower than VRC01 (32%). VRC01-class heavy chains could evolve within 2 years, but light chain maturation was stalled. The structural analysis revealed that the clash of LCDR1 and N terminus with the N276 and V5 glycans, which could well explain the limited neutralizing activity and the stalled lineage development. The N-terminal truncation of DRVIA7 light chain and introduction of the VRC01 LCDR1 significantly increased the neutralizing potency and breadth. When DRVIA7 heavy chain was paired with VRC01 light chain, the antibody acquired abroader neutralizing breadth than VRC01 and could neutralize several VRC01-resistant virus.
The research result entitled “Key gp120 glycans pose roadblocks to the rapid development of VRC01-class antibodies within an HIV-1-infected Chinese donor” was featured as the cover story of the journal Immunity on April 19, 2016. This study captured the early events in the emergence and the whole processin the maturity of this antibody class for the first time, which filled the international gap in this field. The evolution of heavy and chain chains were not synchronous. The VRC01-like neutralizing heavy chain precursors could rapidly matured within 2 years, however, the evolution of light chain might need longer time. The virus used idiomaticglycan shield mechanism to escape the immune system and stall the antibody light chain maturation. These specialized antibody heavy chains could evolve in just two years, which made researchers to believe that effective HIV vaccine eliciting bNAbs could be developed in future. The study revealed that HIV disturbed the maturation of light chain, which made researchers to pay more attention to light chain evolution, especially the influence of key gp120 glycans. The new knowledge of the evolution and key traits of anti-HIV antibodies could help researchers design a vaccine to prevent AIDS.
This international cooperation's work was supported by the National Major projects for Infectious Diseases Control and Prevention and NIH HIV Vaccine Research program. This work had also benefited from previous international cooperation funds of Ministry of Science and Technology and the NIH CIPRA grant. The Dr. Shao group established a long-term cooperative relationship with Anhui Provincial Center for Disease Control and Prevention etc. By tracking study of HIV-1-infected donors in China, the Dr. Shao group screened outseries of elite controllers. This is the first time that a VRC01-like antibody could be isolated from a patient of Asian descent, meaning that people with different genetic backgrounds could generate this class of bNAbs. This study also provided a series of bNAbs, which might be used as immunotherapeutic agents for AIDS treatment and prevention in future. The scientists and institutes in China and the United States had applied for the patents of these bNAbs before publication.
In cooperation with the scientists at the Scripps Research Institute, Dr. Yiming Shao group at the Chinese Center for Disease Control and Prevention had systematically researched bNAbs within an HIV-1-infected Chinese donor. A CD4 binding site directed at antibody-DRVIA7 was isolated using single B cell sorting and monoclonal antibody expression technology. Dynamic antibody evolution was revealed by unbiased analysis of B cell repertoires. This study captured the process of this lineage antibody from birth to mature. Gene sequence analysis revealed that the heavy chain of DRVIA7 was IgHV1-02*02 allelic origin with a SHM of 19% which was lower than VRC01 (32%). VRC01-class heavy chains could evolve within 2 years, but light chain maturation was stalled. The structural analysis revealed that the clash of LCDR1 and N terminus with the N276 and V5 glycans, which could well explain the limited neutralizing activity and the stalled lineage development. The N-terminal truncation of DRVIA7 light chain and introduction of the VRC01 LCDR1 significantly increased the neutralizing potency and breadth. When DRVIA7 heavy chain was paired with VRC01 light chain, the antibody acquired abroader neutralizing breadth than VRC01 and could neutralize several VRC01-resistant virus.
The research result entitled “Key gp120 glycans pose roadblocks to the rapid development of VRC01-class antibodies within an HIV-1-infected Chinese donor” was featured as the cover story of the journal Immunity on April 19, 2016. This study captured the early events in the emergence and the whole processin the maturity of this antibody class for the first time, which filled the international gap in this field. The evolution of heavy and chain chains were not synchronous. The VRC01-like neutralizing heavy chain precursors could rapidly matured within 2 years, however, the evolution of light chain might need longer time. The virus used idiomaticglycan shield mechanism to escape the immune system and stall the antibody light chain maturation. These specialized antibody heavy chains could evolve in just two years, which made researchers to believe that effective HIV vaccine eliciting bNAbs could be developed in future. The study revealed that HIV disturbed the maturation of light chain, which made researchers to pay more attention to light chain evolution, especially the influence of key gp120 glycans. The new knowledge of the evolution and key traits of anti-HIV antibodies could help researchers design a vaccine to prevent AIDS.
This international cooperation's work was supported by the National Major projects for Infectious Diseases Control and Prevention and NIH HIV Vaccine Research program. This work had also benefited from previous international cooperation funds of Ministry of Science and Technology and the NIH CIPRA grant. The Dr. Shao group established a long-term cooperative relationship with Anhui Provincial Center for Disease Control and Prevention etc. By tracking study of HIV-1-infected donors in China, the Dr. Shao group screened outseries of elite controllers. This is the first time that a VRC01-like antibody could be isolated from a patient of Asian descent, meaning that people with different genetic backgrounds could generate this class of bNAbs. This study also provided a series of bNAbs, which might be used as immunotherapeutic agents for AIDS treatment and prevention in future. The scientists and institutes in China and the United States had applied for the patents of these bNAbs before publication.
