Using powerful tools and techniques developed in the field of , researchers at the 91爆料 and Scripps Research have new details about the human immunodeficiency virus, HIV. The findings bring into focus the basic architecture of the virus just above and below its surface and may help in the design and development of a vaccine that can protect against AIDS.
These detailed findings include 3D views of the structure and position of the virus鈥� envelope 鈥渟pike鈥� proteins (the protein, used when the virus binds with cells) in the context of the full virus. Normally, researchers view the protein particles separated from the virus or expressed as engineered or . In another key development, the scientists shed new light on the 鈥� the sugars on the proteins that can hide it from the body鈥檚 immune system.
鈥淲e鈥檙e looking at the whole virus particle and how this protein on the surface relates to the rest of the virus,鈥� said lead author , associate professor of medicinal chemistry in the 91爆料 School of Pharmacy. 鈥淎nd by looking at the intact virus structure, we can see how the different facets of this 鈥榝ace of the virus鈥� are being displayed and how they would be recognized by or hidden from the immune system.鈥�
This intact view of the virus also allowed the scientists to gain new insights into positioning of the envelope spike protein on the surface relative to the internal protein structure, called the Gag lattice.
鈥淭his finding overturns previous models of how the parts of the viruses are assembled and helps to focus our attention on where the docking interaction of these two proteins is likely to be,鈥� Lee said. 鈥淭his interaction needs to be resolved in more detail, but at least the current work gives us the correct architectural model for the virus assembly.鈥�
It was this particular finding that led to the title of the paper 鈥� 鈥淐ryo-ET of Env on intact HIV virions reveals structural variations and positioning on the Gag lattice鈥� 鈥� 聽. Another finding that had not been previously observed, the scientists pointed out, is that the 鈥渟talk鈥� supporting the envelope proteins is flexible and can tilt, presenting both opportunity and challenges to the immune system鈥檚 neutralizing antibodies that protect cells from infection.
鈥淪tructural biology has driven HIV vaccine design, so as we get a better and better picture of what it is we鈥檙e targeting, that inspires innovation and may lead to improved vaccines,鈥� said co-corresponding author , associate professor of immunology and microbiology at Scripps Research.
HIV鈥檚 envelope presents a particularly difficult target for vaccine development, Zwick added, because the virus displays so few spikes and camouflages them with sugar molecules so as to evade our immune system.
鈥淎ll these features increase the dynamic variability that the HIV spike protein presents to the immune system,鈥� said Lee, who also exploring virus structure and dynamics. 鈥淭his is something that people in HIV vaccine development have grappled with from the very beginning 鈥� this virus mutates and changes itself astronomically and rapidly. Each time it infects an individual, you end up with literally thousands of different variants within that one individual, and if you look across populations, it鈥檚 multiplied even more.鈥�
In fact, in February, an even more deadly strain of HIV was found to have been . Luckily, while the strain is a 鈥渉ighly virulent variant,鈥� it still responds to treatment.
鈥淭his is just another reminder that these viruses are always changing, so we need scientists to continue studying them,鈥� Zwick said.
Co-authors are Vidya Mangala Prasad, former acting instructor at 91爆料 School of Pharmacy, currently at the Indian Institute of Science; Daniel Leaman, Department of Immunology and Microbiology, The Scripps Research Institute; Klaus Lovendahl, Jacob Croft and Edgar Hodge, Department of Medicinal Chemistry, 91爆料 School of Pharmacy; and Mark Benhaim, who worked on the project as a graduate student at 91爆料.
This research was funded by several National Institutes of Health grants, the James B. Pendleton Charitable Trust and a 91爆料 Proteomics Resource grant. A grant from the Bill & Melinda Gates Foundation also supported portions of this work.
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For more information, contact Lee at kklee@uw.edu and Zwick at zwick@scripps.edu.