Towards a universal HIV vaccine with the identification of first immature ‘elite controller’ antibody.


HIV has been hard to beat as the virus mutates rapidly and has a sturdy set of defenses, including a ‘shield’ of glycan molecules on the surface of its envelope glycoproteins. These glycoproteins are the viral machinery used to make initial contact and subsequently infect human host cells.  Because HIV presents such a challenge to the immune system, scientists can’t use traditional methods to create a vaccine.

Instead, they have to reverse engineer the right vaccine candidates using rare effective antibodies from HIV-positive patients as guides.  Now, a study from researchers led by The Scripps Research Institute (TSRI) identifies the first-ever immature or ‘teenage’ antibody found in a powerful class of immune molecules effective against HIV.  The team state that the new knowledge of the evolution and key traits of this anti-HIV antibody could help researchers design a vaccine to prevent AIDS.  The opensource study is published in the journal Immunity.

Previous studies show that VRC01-class antibodies neutralize diverse HIV-1 strains by targeting the conserved CD4-binding site. Despite extensive investigations, crucial events in the early stage of VRC01 development remain elusive.  The antibody in the current study came from a patient in China who was what scientists call an ‘elite’ controller, meaning the patient’s immune system had managed to create antibodies with some ability to fight the disease. The patient was among the top 5% of neutralizers assessed in a screening of hundreds of Chinese HIV patients by China CDC scientists.  The current study shows that genetically, the antibody found in this donor resembled members of the VRC01 class of antibodies, which are broadly neutralizing antibodies, named for their ability to target a key site of vulnerability on many strains of the virus; yet the new antibody also lacked one of the key structural traits of VRC01 antibodies.

The current study into the antibody’s genetics and structure showed that it is a precursor to mature VRC01 antibodies, in other words, it represented a middle stage in the evolution of this class of HIV killers.  The lab named the antibody a ‘teenager’ and state that it provides a unique view of the steps needed to prompt the immune system to effectively target HIV.  The group studied samples taken from the patient over five years, with each sample showing the antibody in a different stage of development, providing a possible guide to elicit these antibodies with a vaccine.

Results show that the antibody evolved rapidly between 2006 and 2008, gaining many of the traits it would need to fight HIV. The team note that this finding contradicts previous studies suggesting that it can take up to 10 to 15 years for VRC01 antibodies to develop useful traits.  Data findings show that these specialized antibodies can evolve in just one or two years.  The researchers state that they spotted a hurdle they will have to overcome as they engineer their own antibodies, namely, the teenage VRC01 has a slightly longer amino acid chain at one site than the mature version, and this chain clashes with part of the glycoprotein shield (gp120) on HIV and prevents the antibody from effectively neutralizing the virus.

The team surmise that they have shown it is possible to tweak the immature antibody to make it into a broadly neutralizing antibody.  They go on to note that this is the first time a VRC01-like antibody has been isolated from a patient of Asian descent, the other VRC01s had come from African or Caucasian patients.  For the future, the researchers state that this means people with different genetic backgrounds may benefit from a vaccine that harnesses a person’s ability to make VRC01s.  They conclude that this could be important for developing a universal HIV vaccine.

Source: The Scripps Research Institute (TSRI) 

 

VRC01-class antibodies neutralize diverse HIV-1 strains by targeting the conserved CD4-binding site. Despite extensive investigations, crucial events in the early stage of VRC01 development remain elusive. We demonstrated how VRC01-class antibodies emerged in a Chinese donor by antigen-specific single B cell sorting, structural and functional studies, and longitudinal antibody and virus repertoire analyses. A monoclonal antibody DRVIA7 with modest neutralizing breadth was isolated that displayed a subset of VRC01 signatures. X-ray and EM structures revealed a VRC01-like angle of approach, but less favorable interactions between the DRVIA7 light-chain CDR1 and the N terminus with N276 and V5 glycans of gp120. Although the DRVIA7 lineage was unable to acquire broad neutralization, longitudinal analysis revealed a repertoire-encoded VRC01 light-chain CDR3 signature and VRC01-like neutralizing heavy-chain precursors that rapidly matured within 2 years. Thus, light chain accommodation of the glycan shield should be taken into account in vaccine design targeting this conserved site of vulnerability.  Key gp120 Glycans Pose Roadblocks to the Rapid Development of VRC01-Class Antibodies in an HIV-1-Infected Chinese Donor.  Shao et al 2016.

VRC01-class antibodies neutralize diverse HIV-1 strains by targeting the conserved CD4-binding site. Despite extensive investigations, crucial events in the early stage of VRC01 development remain elusive. We demonstrated how VRC01-class antibodies emerged in a Chinese donor by antigen-specific single B cell sorting, structural and functional studies, and longitudinal antibody and virus repertoire analyses. A monoclonal antibody DRVIA7 with modest neutralizing breadth was isolated that displayed a subset of VRC01 signatures. X-ray and EM structures revealed a VRC01-like angle of approach, but less favorable interactions between the DRVIA7 light-chain CDR1 and the N terminus with N276 and V5 glycans of gp120. Although the DRVIA7 lineage was unable to acquire broad neutralization, longitudinal analysis revealed a repertoire-encoded VRC01 light-chain CDR3 signature and VRC01-like neutralizing heavy-chain precursors that rapidly matured within 2 years. Thus, light chain accommodation of the glycan shield should be taken into account in vaccine design targeting this conserved site of vulnerability. Key gp120 Glycans Pose Roadblocks to the Rapid Development of VRC01-Class Antibodies in an HIV-1-Infected Chinese Donor. Shao et al 2016.

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