The Advanced Photon Source
a U.S. Department of Energy Office of Science User Facility

A small, but very fast, step toward a vaccine against HIV

A series of diagrams of shapes representing the HIV glycoprotein, showing the steps between the closed and open states.

Human immunodeficiency virus 1 (HIV-1) was discovered and identified as the causative agent of acquired immune deficiency syndrome (AIDS) in the early 1980s and researchers have been trying to find an effective vaccination strategy against it ever since. Even compared to other crafty viruses that evolve rapidly to avoid immune detection, HIV has a remarkable ability to evade our immune system. This is demonstrated by the fact that the protein that mediates viral fusion to host cells, the viral envelope glycoprotein (ENV), is poorly recognized by the immune system, making its use as an immune system activator for vaccination efforts a challenge.

Efforts to understand the structural basis for this immune evasion have also been challenged by the glycoprotein’s poor solubility and instability that have made it difficult to purify and crystallize. In 2000, researchers advanced the field by adding disulfide bridge structures and mutations that stabilized the protein in solution, but it was another 13 years before the first X-ray structures of ENV were solved and structure-based vaccine design could begin to address the challenges of vaccine development.

Fast-forward to 2024 and a vaccine has still not been developed that provides broad protection against the virus. However, even with effective anti-retroviral treatment that can give AIDS patients an almost normal lifespan, 1.5 million people are newly infected each year and a preventive vaccine is still urgently needed. Research from a team at Duke University and the University of Chicago using time-resolved, temperature-jump, small-angle X-ray scattering (SAXS) at the University of Chicago’s BioCARS 14-ID-B beamline at the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science user facility at DOE’s Argonne National Laboratory, has provided new findings on the microsecond dynamics of the ENV structure that could jumpstart the next round of vaccine development.

The basics of the HIV glycoprotein’s interaction with the host cell have been elucidated by previous structure studies. The ENV glycoprotein has two subunits, gp120 and gp41, that mediate interactions with T cells of the immune system. Initial binding to a receptor, CD4, and a co-factor on T cells is mediated by gp120 while gp41 mediates fusion of the virus with the host cell. Before receptor binding, gp120 surrounds gp41 to keep the fusion machinery quiescent before engagement of the host cell in a stable “closed” state. Once gp120 binds CD4, it rotates to expose gp41 and activates fusion, resulting in a more disordered “open” state. The structures of these states have been solved but nothing is known about possible intermediate states. This is important because it is widely believed that preventing this transition from the closed state to the open state is essential to creating a vaccine capable of generating a robust immune response that blocks disease transmission.

In order to identify possible structural intermediates in this transition, the team studied two of the stabilized forms of the ectodomain of ENV responsible for host cell interactions at microsecond time scales. After first showing they could detect the open and closed configurations and confirming structural information using structure-sensitive antibodies, they next looked for intermediates. Analysis of the SAXS data revealed a rapid order-to-disorder transition at a key latch that holds the trimer closed in the microsecond timescale (Figure 1). They observed that larger domain rearrangements to an open-like state occurred on a much longer timescale, a full two orders of magnitude longer than the rapid initial formation of the intermediate.

Once the rapidly forming intermediate was identified, the team was able to use this information to block the transition to the open state by engineering an ENV protein that could not adopt the transitional intermediate, demonstrating that the intermediate is essential to the transition to the open state that leads to virus fusion. The team hopes that the discovery of this rapid initial step in the fusion process will be beneficial to the ongoing efforts to develop an effective prophylactic vaccine for HIV-1. – Sandy Field

See: A.L. Bennett1, R.J. Edwards1, I. Koshelva2, C. Saunders1, Y. Bililign1,  A. Williams1, P. Bubphamala1, K. Manosouri1, K. Anasti1, K.O. Saunders1,3, S.M. Alam1,3,4, B.F. Haynes1,3, P. Acharya1,2,5, R. Henderson1,3, “Microsecond dynamics control the HIV-1 envelope conformation,” Sci Adv 10, 5 (February 2024)

Author affiliations: 1Duke Human Vaccine Institute, Duke University Medical Center; 2BioCARS, University of Chicago; 3Duke University Medical Center; 4Duke University School of Medicine; 5Duke University.

This project was supported by NIH, National Institute of Allergy and Infectious Diseases, Division of AIDS Consortia for HIV/AIDS Vaccine Development (CHAVD) grants UM1AI144371 (to B.F.H.), R01AI145687 (to P.A.), and U54AI170752 (to R.H. and P.A.) and Translating Duke Health Initiative (to R.H. and P.A.). A portion of this work was conducted at the Advanced Light Source (ALS), a national user facility operated by Lawrence Berkeley National Laboratory on behalf of the US Department of Energy (DOE), Office of Basic Energy Sciences, through the Integrated Diffraction Analysis Technologies (IDAT) program, supported by DOE Office of Biological and Environmental Research. Additional support comes from the NIH project ALS-ENABLE (P30 GM124169) and a High-End Instrumentation Grant S10OD018483. This research also used resources of the Advanced Photon Source, a DOE Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. The use of BioCARS was also supported by the National Institute of General Medical Sciences ( of the NIH ( under grant number P41 GM118217. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. TR setup at Sector 14 was funded in part through a collaboration with P. Anfinrud (NIH/NIDDK). A part of this work was conducted at the ALS, a national user facility operated by Lawrence Berkeley National Laboratory on behalf of the DOE, Office of Basic Energy Sciences, through the IDAT program, supported by DOE Office of Biological and Environmental Research. Additional support comes from the NIH project ALS-ENABLE (P30 GM124169) and a High-End Instrumentation Grant S10OD018483.

The U.S. Department of Energy's APS at Argonne National Laboratory is one of the world’s most productive x-ray light source facilities. Each year, the APS provides high-brightness x-ray beams to a diverse community of more than 5,000 researchers in materials science, chemistry, condensed matter physics, the life and environmental sciences, and applied research. Researchers using the APS produce over 2,000 publications each year detailing impactful discoveries and solve more vital biological protein structures than users of any other x-ray light source research facility. APS x-rays are ideally suited for explorations of materials and biological structures; elemental distribution; chemical, magnetic, electronic states; and a wide range of technologically important engineering systems from batteries to fuel injector sprays, all of which are the foundations of our nation’s economic, technological, and physical well-being.

Argonne National Laboratory seeks solutions to pressing national problems in science and technology. The nation's first national laboratory, Argonne conducts leading-edge basic and applied scientific research in virtually every scientific discipline. Argonne researchers work closely with researchers from hundreds of companies, universities, and federal, state and municipal agencies to help them solve their specific problems, advance America's scientific leadership and prepare the nation for a better future. With employees from more than 60 nations, Argonne is managed by UChicago Argonne, LLC, for the U.S. DOE Office of Science.

The U.S. Department of Energy's Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time. For more information, visit the Office of Science website.

Published Date