The first efficacy trial of an HIV vaccine, AIDSvax, began in 1998. This vaccine, which contained the gp120 envelope glycoprotein of the virus, proved to be ineffective. The difficulty of vaccine candidates to elicit effective immune responses relate to the ability of HIV to confound the humoral immune system with its viral spike, which is composed of three gp120 envelope glycoproteins and three gp41 transmembrane molecules. Despite eliciting high titers of antibodies, the spike is impervious to neutralization: although strain-specific antibodies can be raised, the elicitation process is rapidly outstripped by viral diversity. How the virus is able to maintain highly specific receptor interactions, while avoiding antibody recognition, is key to its ability to maintain a persistent infection – and a central conundrum in the search for a vaccine. In their commentary, Drs. Kwong and Sodroski describe the insights they gained from the first crystal structure of the HIV gp120 envelope glycoprotein that they obtained in 1998.
Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody.
Nature. 1998 Jun 18;393(6686):648-59.
Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA.
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Commentary by Drs. Kwong and Sodroski
The structure of the HIV-1 gp120 envelope glycoprotein, published on June 18, 1998 as a Nature article, provided the first atomic-level description of the part of the virus responsible for attaching to cells, triggering entry, and evading antibodies. We were fortunate to catch gp120 in the act of grabbing onto its primary cell receptor, CD4, and with a human antibody locked onto the site of co-receptor binding. The structure provided the first link between accumulating genetic information on the virus and chemical details of its entry behavior and immune evasion: an atom-by-atom view of the interaction with CD4; unusual surface pockets and domain structure suggestive of conformational change; and definition of the residues that make up its antigenic surface (allowing for a description of the antigenic structure of gp120, which showed how the virus uses N-linked glycosylation and surface variability to make itself invisible to the humoral immune response, and published as a separate paper in the same issue of Nature).
The structure of gp120 had been a long-sought goal, as it was clear that it was needed to provide a chemical description of HIV-1 entry and immune evasion – a description that would allow mechanistic understanding and facilitate approaches to intervention. The heralded accomplishments of structure-based drug design targeting the HIV-1 protease demonstrated the importance of this information – with the added twist that some form of HIV-1 gp120 would likely be the immunogen needed for an effective HIV-1 vaccine. The problem was that the gp120 protein was highly flexible in conformation, covered with variable loops, and masked by N-linked glycan – the same molecular trickery that allowed it to evade the human immune response also prevented crystallization and X-ray analysis. The solution that we used – radical modification of the gp120 surface – has proven to retain much of the underlying biology associated with this envelope protein.
The gp120 structure comprises many short segments of secondary structure: 5 alpha-helices, 25 beta-strands, and 10 loops, in just a little over 300 residues. The large size of the CD4-binding surface was a surprise – and it took several years to understand how it evades most antibody-mediated recognition. Of note, the structure revealed a large pocket in gp120 at the site of CD4 binding that represented an attractive potential target for inhibitors. The immunological silence of the glycan-rich outer surface was another surprise – and engineered immunosilencing is just now being incorporated into the design of gp120-based vaccine immunogens.
The work described in the Nature papers led to a rapid characterization of the conserved gp120 binding site for the coreceptors, CCR5 and CXCR4. This paper, and a review of the HIV-1 envelope glycoproteins that benefitted from the new structural information, was published a day later in Science. The gp120 glycoprotein became the first (and only) structure to be published simultaneously on the covers of both Nature and Science.
Thirteen years later, the implications of the gp120 structure are still being realized. With respect to our understanding of the HIV-1 entry mechanism, many details have been added over the years, but the initial structure encompassed the bulk of our current appreciation of this process. This is in part because the original structure showed the majority of the core (defining 3/5 of the overall gp120 structure) and because the structure of the entire viral envelope glycoprotein spike has proven so difficult to obtain (it is still not determined). In the area of therapeutics, although the structure has led to the development of tight binding compounds, no structure-based drug has yet made it through clinical trials. In the vaccine area, although the structure spurred the development of many immunogens, it was not until the last few years that epitopes for broadly neutralizing antibodies have been identified. These findings reveal that extensive antibody maturation is required for recognition, a hurdle that is just now being attacked.
About the authors: Peter D. Kwong began this work as a graduate student in Wayne A. Hendrickson’s laboratory at Columbia University and is currently Chief of the Structural Biology Section of the Vaccine Research Center, NIAID/NIH. Joseph Sodroski was (and continues to be) a professor in the Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School.
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