In the Journals

Researchers investigate early stages of HIV-neutralizing antibody

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April 8, 2016

Scientists at The Scripps Research Institute and collaborating institutions have identified and characterized an immature, or “teenage,” antibody with broadly neutralizing signatures isolated from an elite controller. The researchers said their findings, published in Immunity, may be useful for future HIV vaccine development.

“This is actually the first example of how we can go back to the really early stage to see how this particular antibody lineage was born and can develop,” TSRI researcher and biologist Jiang Zhu, PhD, said in a press release.

Zhu and research colleagues from the University of Maryland, the China CDC, Peking University and Nankai University extracted a monoclonal antibody with a subset of broadly neutralizing antibody (bNAb) signatures resembling the VRC01 class from a Chinese patient with HIV. The patient was among the top 5% of neutralizers screened by China CDC researchers, according to the press release. It is the first time a VCR01-like antibody had been isolated from a patient of Asian descent.

“This could be important for developing a universal HIV vaccine,” Zhu said in the release.

An analysis of the antibody’s structure revealed “critical differences” between the patient’s monoclonal antibody DRVIA7 and VRC01-like antibodies in the light chain CDR1 and N-terminus, both of which interact with glycoprotein 120 (gp120) of the HIV-1 envelope trimer — an “ideal” target for vaccine development, the researchers wrote. Previous research has shown VRC01 antibodies neutralize HIV-1 isolates by binding strongly to the gp120. A functional analysis of DRVIA7, however, showed the interaction between DRVIA7 light chain CDR1 and N276 and V5 glycans on gp120 prevented broadly neutralizing activity. Structurally, DRVIA7 had a slightly longer and germline-like light chain CDR1 compared with a matured VRC01 antibody, Zhu told Infectious Disease News.  

“These findings suggested that DRVIA7 might be a VRC01-class antibody that had acquired a subset of VCR01 signatures but not yet broad neutralizing activity, thus providing an opportunity to study the emergence of VRC01-class antibodies,” Zhu and colleagues wrote.

The researchers examined the emergence of DRVIA7 over 5 years. They observed functional VRC01-like neutralizing heavy chain precursors in 2006, placing the “birth date” of DRVIA7 lineage shortly before then. By 2008, the average heavy chain somatic hypermutation increased from 17% to 22.9%, with some heavy chain precursors having an approximate 13% mutation level, Zhu told Infectious Disease News. This finding indicates the immune system is capable of rapidly maturing VRC01-like heavy chains within 2 years, which contradicts previous research suggesting useful traits of VRC01 antibodies can take a long time (roughly 10 to 15 years) to mature, he said.

Despite this, full maturation of heavy chains did not occur naturally, the researchers wrote. Instead, they re-engineered the N-terminus and light chain complementarity-determining region 1 of DRVIA7. The tweaked antibody had then advanced from limited neutralization breadth to a bNAb.

“As long as you have those critical VRC01 signatures, a teenage-stage antibody can become a killer for HIV,” Zhu said in the press release.

The researchers concluded that light chain accommodation of the glycan shield should be considered during vaccine development. – by Stephanie Viguers

Disclosure: The researchers report no relevant financial disclosures.