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.
Commentary by Drs. Kwong and Sodroski
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 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.
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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