HIV-1 Neutralizing Antibodies

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HIV, human immunodeficiency virus, infection is one of the most pressing global human health problems for which we do not currently have cost-effective solutions. According to World Health Organization estimates HIV currently infects about 34 million people globally, 10 percent of whom are children. Although antiviral drugs are now used to manage many HIV infections, especially in developed countries, scientists have long sought a vaccine that can prevent new infections and would help perhaps to ultimately eradicate the virus from the human population. However, none of the HIV vaccines tested so far has come close to providing adequate protection. This failure is due largely to the challenges posed by HIV’s envelope protein, known to virologists as Env. The enormous variability of Env has made the development of a vaccine a tremendous and so far elusive challenge. Nonetheless, many more highly potent broadly neutralizing antibodies (bnAbs) against HIV have recently been discovered, which provide important clues in the quest for such a vaccine as well as for inhibitor design. Deciphering the molecular basis of interaction between the viral epitopes on the Env protein (gp120/gp41) and bnAbs using primarily X-ray crystallography and electron microscopy (EM) has revealed a greater number of sites of vulnerability on the virus than previously anticipated. Simply stated, the three-dimensional structures of HIV-1 Env proteins in complex with bnAbs have vividly illustrated the highly creative ways that the human immune system can find to penetrate the ever-changing viral defenses.

 Recently, in collaboration with the  Weill Cornell Medical College, we have determined the first atomic-level structure of the tripartite HIV envelope protein—long considered one of the most difficult targets in structural biology and of great value for medical science. The new data provide the most detailed picture yet of the AIDS-causing virus’s complex envelope, including sites that future vaccines will try to mimic to elicit a protective immune response. Most of the prior structural studies of this envelope complex focused on individual subunits, but we’ve needed the structure of the full complex to properly define the sites of vulnerability that could be targeted, for example with a vaccine.

HIV’s Env is not a single, simple protein but rather a “trimer” made of three identical, loosely connected structures with a stalk-like subunit, gp41, and a cap-like region, gp120. Each trimer resembles a mushroom and up to about 15 of these Env trimers sprout from the membrane of a typical virus particle, ready to latch onto susceptible human cells and facilitate viral entry. Although Env in principle is exposed to the immune system, in practice it has evolved highly effective strategies for evading immune attack. It frequently mutates its outermost “variable loop” regions, for example, and also coats its surfaces with hard-to-grip sugar molecules (also called glycans). Even so, HIV vaccine designers might have succeeded by now, had they been able to study the structure of the entire Env protein at atomic-scale—in particular, to fully characterize the sites where the most effective virus-neutralizing antibodies bind. These studies have great insights for accelerating HIV-1 vaccine research. However, the challenge still remains as to how to elicit such bnAbs in a vaccine setting.

    1. Julien, J. – P., Cupo, A., Sok, D., Stanfield, R. L., Lyumkis, D., Deller, M. C., et al. (2013). Crystal Structure of a Soluble Cleaved HIV-1 Envelope Trimer. Science.
    2. Lyumkis, D., Julien, J. – P., de Val, N., Cupo, A., Potter, C. S., Klasse, P. – J., et al. (2013). Cryo-EM Structure of a Fully Glycosylated Soluble Cleaved HIV-1 Envelope Trimer. Science.
    3. Jardine, J., Julien, J. – P., Menis, S., Ota, T., Kalyuzhniy, O., McGuire, A., et al. (2013). Rational HIV immunogen design to target specific germline B cell receptors. Science340, 711–716.
    4. Julien, J. – P., Lee, J. H., Cupo, A., Murin, C. D., Derking, R., Hoffenberg, S., et al. (2013). Asymmetric recognition of the HIV-1 trimer by broadly neutralizing antibody PG9. Proc Natl Acad Sci U S A110, 4351–4356.
    5. Julien, J. – P., Sok, D., Khayat, R., Lee, J. H., Doores, K. J., Walker, L. M., et al. (2013). Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans. PLoS Pathog9, e1003342.
    6. Khayat, R., Lee, J. H., Julien, J. – P., Cupo, A., Klasse, P. J., Sanders, R. W., et al. (2013). Structural Characterization of Cleaved, Soluble HIV-1 Envelope Glycoprotein Trimers. J Virol87, 9865–9872.
    7. Klasse, P. J., Depetris, R. S., Pejchal, R., Julien, J. – P., Khayat, R., Lee, J. H., et al. (2013). Influences on Trimerization and Aggregation of Soluble, Cleaved HIV-1 SOSIP Envelope Glycoprotein. J Virol87, 9873–9885.
    8. Kong, L., Lee, J. H., Doores, K. J., Murin, C. D., Julien, J. – P., McBride, R., et al. (2013). Supersite of immune vulnerability on the glycosylated face of HIV-1 envelope glycoprotein gp120 (Vol. 20).
    9. Ringe, R. P., Sanders, R. W., Yasmeen, A., Kim, H. J., Lee, J. H., Cupo, A., et al. (2013). Cleavage strongly influences whether soluble HIV-1 envelope glycoprotein trimers adopt a native-like conformation. Proc Natl Acad Sci U S A, .
    10. Sanders, R. W., Derking, R., Cupo, A., Julien, J. – P., Yasmeen, A., de Val, N., et al. (2013). A Next-Generation Cleaved, Soluble HIV-1 Env Trimer, BG505 SOSIP.664 gp140, Expresses Multiple Epitopes for Broadly Neutralizing but Not Non-Neutralizing Antibodies. PLoS Pathog9, e1003618.
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