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A family affair
LA JOLLA, Calif.—HIV poses a variety of challenges, not just for its virulence, but also for the complexity of the virus itself. The vulnerable sites of the HIV virus are covered with a surface envelope protein (Env) that is capable of mutating from strain to strain; in addition, the surface of the virus is coated with glycans that make it difficult for antibodies to latch onto.
However, there are some sites on the HIV virus that remain largely the same between strains, due to the fact that they are involved in key viral functions, and in some cases, the immune system can eventually get past the glycans to produce antibodies that can bind to such sites. Though these “broadly neutralizing” antibodies generally aren't produced in high-enough quantities to provide a significant benefit, they are still thought to hold promise.
That promise is the focus of some of the most recent HIV research, including a new study from The Scripps Research Institute (TSRI) that investigated how broadly neutralizing antibodies come to be and how they serve to target multiple strains of the HIV virus. The work was a collaboration between the labs of TSRI Prof. Dennis R. Burton, director of the International AIDS Vaccine Initiative’s Neutralizing Antibody Consortium and the National Institutes of Health-sponsored Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery at TSRI, and Ian A. Wilson, Hansen Professor of Structural Biology, chair of the Department of Integrative Structural and Computational Biology and member of the Skaggs Institute for Chemical Biology at TSRI.
The hope behind this research is to retroactively engineer an HIV vaccine—specifically, that by studying the end results of antibody generation, it will one day be possible to trace the mutations back to the original antibody.
This study focused on characterizing the antibody PGT124, which comes from the same family as PGT 121, though on a different 'branch,' so to speak. PGT121 was recently shown to protect monkeys from infections with simian HIV and to lower viral levels in monkeys that were already infected.
The PGT121 antibody family, like others of its kind, is the result of a diversity-extending process by the immune response that is known as affinity maturation. In normal situations, even when no infection is present, B cells in the immune system produce millions of “germline” antibodies. However, when one of those B cells comes across a matching target, activates and begins to replicate, its antibody-coding genes mutate slightly with each cell division.
In previous work, it was established that several antibodies in this family—PGT121-123—target a vulnerable site on the Env protein at the base of the hypervariable structure known as the V3 loop, binding to protein components that vary little, as well as multiple glycans, though they present with low affinity for any one glycan. This recent study demonstrated that a sibling antibody, PGT124, can bind to the virus by attaching to a small fragment of the viral protein and a solitary glycan.
“This gives us better detail on how PGT121 family antibodies have diverged during the affinity maturation process—it’s clear that there are multiple pathways, even within a single antibody family, to achieve broad neutralization of HIV. That’s important to understand for vaccine design for HIV, as well as other glycan-shielded viruses such as influenza and hepatitis C virus. It’s also relevant to the problem of targeting glycan structures on cancers and other diseases,” Devin Sok, a research associate in the Burton laboratory, commented in a press release.
As noted in the paper, “Affinity maturation then leads to divergent evolutionary branches that either focus on a single glycan and protein segment (e.g., Ab PGT124) or engage multiple glycans (e.g., Abs PGT121–123). Furthermore, other surrounding glycans are avoided by selecting an appropriate initial antibody shape that prevents steric hindrance. Such molecular recognition lessons are important for engineering proteins that can recognize or accommodate glycans.” The end result of affinity maturation is a family of closely related B cells and corresponding antibodies that can potentially hit the same target more strongly, precisely and in different ways. Despite the work done in this area, it is still unknown which germline antibody develops into the PGT121 family.
“Affinity maturation is a critical process of directed evolution in mounting an antibody response to all pathogens. However, molecular details of this process have been unavailable. Now, through structural biology, we have elucidated at the atomic level how antibody maturation can pursue different strategies to recognize HIV-1 gp120, leading to broad neutralization of the virus,” Fernando Garces, a postdoctoral fellow in the Wilson laboratory, noted in a statement. “Initially, we had assumed that the PGT121 family has a complex epitope involving multiple protein pieces and many glycans. So when the crystal structure first popped out on my computer screen and I saw the antibody binding to a single glycan, my first thought was it was wrong. Later we confirmed that the PGT124 antibody does indeed require only a single glycan and a few surrounding amino acids on the envelope protein to neutralize up to 70 percent of all HIV-1 strains.”
The study, “Structural Evolution of Glycan Recognition by a Family of Potent HIV Antibodies,“ appeared in the journal Cell on Sept. 25.
This is the latest of several papers from TSRI in the area of HIV research in recent months. In July, the institute posted news of a pair of studies: one headed by Burton, the other co-headed by Wilson. Those papers worked with the Env protein as well, in addition to the PGT151 and 152 antibodies, two other broadly neutralizing options. (For the full story, check out “Nailing down Env in HIV.” link: http://www.ddn-news.com/index.php?newsarticle=8626 )