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Researchers Identify Early-Stage HIV-Neutralizing Antibody

NEW YORK (GenomeWeb) – In a step toward figuring out how to design a vaccine for HIV, researchers have identified and characterized a known HIV-neutralizing antibody in an early stage of its development.

The work, which involved researchers from the Scripps Research Institute, the University of Maryland, the Chinese Center for Disease Control and Prevention, Peking University and Nankai Univeristy, was published online today in the journal Immunity.

The class of broadly HIV-neutralizing antibodies known as VRC01 was discovered in 2010, yet despite extensive research, how those antibodies develop in individuals has been relatively unknown. Now, however, researchers have used cell sorting, viral repertoire sequencing, and functional and structural studies to better characterize a VRC01 antibody in the early stages of development in a Chinese patient with HIV.

The study is "the first example of how we can go back to the really early stage to see how this antibody lineage was born and can develop," Jiang Zhu, a biologist at the Scripps Research Institute and co-senior author of the study, said in a statement.

The international team of researchers analyzed blood from a Chinese patient with HIV who was a "long-term non-progressor" over a period of five years. They identified a monoclonal antibody known as DRVIA7.

Structural studies showed that the antibody was similar to VRC01, but had "critical differences" in the light chain CDR1 and N-terminus — structures that interact with key proteins responsible for viral entry into cells — that gave DRVIA7 "limited neutralizing activity."

One major hurdle to developing an HIV vaccine has been getting around the glycan proteins that are produced by the virus and bind to immune cells, enabling virus entry. Glycan proteins mutate quickly, evading potential antibodies.

Next, the researchers traced the antibody's lineage using next-generation sequencing to characterize the viral repertoires, and performed single-genome amplification to better understand viral co-evolution.

The team sequenced the patient's B cell repertoire from blood collected at three different time points — 2006, 2008, and 2009. They used Thermo Fisher Scientific's 5' rapid amplification of cDNA ends (RACE), and the Ion Torrent PGM to sequence the B cell transcripts.

From the sequencing data, they were able to piece together how elements of the DRVIA7 antibody evolved throughout the three time points, identifying heavy chain amino acids that became more similar to ones found in VCR01, and light chain amino acids that evolved less.

In order to understand the impact of the divergent heavy chains, the researchers selected 30 from the 2009 sample to further analyze. They found that when they paired them with mature VCR01 light chains, the resulting antibodies showed broad neutralization, "confirming that these heavy chains are indeed VRC01-like," the authors wrote.

"Our analysis revealed a large population of VRC01-like antibodies in the 2009 repertoire containing a DRVIA7 lineage that had not yet overcome the glycan barrier," the authors wrote. By contrast, the earlier repertoire "appeared not to possess the mature VCR01 signature," they added. The team did identify DRVIA7 precursors in the 2006 sample, suggesting that the earliest DRVIA7 antibodies were born prior to 2006.

Interestingly, the researchers found that the antibody lineage evolved rapidly between 2006 and 2008, counter to previous studies that have suggested it could take 10 to 15 years for VCR01 antibodies to develop HIV-neutralizing traits.

The authors wrote that their findings suggest that such VCR01-like antibodies may be present in other patients who have lived long-term with HIV without progressing, and indeed, a subsequent analysis of five such Chinese patients identified "broad serum neutralization after seven to 16 years of infection." As such, "a systematic, unbiased repertoire profiling will likely identify more VRC01-like antibodies from the HIV- 1-infected Chinese cohort," they wrote.