{"id":2448,"date":"2014-11-03T15:40:37","date_gmt":"2014-11-03T14:40:37","guid":{"rendered":"http:\/\/news.embl.de\/?p=2448"},"modified":"2024-11-14T16:31:02","modified_gmt":"2024-11-14T15:31:02","slug":"1411_hiv","status":"publish","type":"post","link":"https:\/\/www.embl.org\/news\/science\/1411_hiv\/","title":{"rendered":"Same pieces, different picture"},"content":{"rendered":"\n

This is not the first time the virus\u2019 structure has challenged scientists\u2019 expectations. In the 1990s, Stephen Fuller at EMBL Heidelberg and colleagues obtained the first cryo-electron microscopy images of immature HIV. The researchers were surprised to discover that the virus did not have a regular symmetrical structure, as had been assumed. This unexpected irregularity posed a challenge that would take decades to overcome. It meant that getting a detailed picture of the structure of the virus\u2019 protein lattice was going to be difficult. Two decades on, by optimising both how data is collected at the microscope and how it is analysed, Florian Schur, a PhD student in John Briggs\u2019 lab<\/a> at EMBL Heidelberg, has now been able to image it at unprecedented detail \u2013 and once again the virus had a surprise in store.<\/p>\n\n\n\n

The structure is definitely different from what we\u2019d expected<\/p><\/blockquote>\n\n\n\n

Working with Barbara M\u00fcller<\/a> and Hans-Georg Kr\u00e4usslich<\/a> at the Heidelberg University Clinic, in the joint Molecular Medicine Partnership Unit<\/a>, Schur and Briggs studied the protein lattice that surrounds the virus\u2019 genetic material. After infecting one of the cells in our immune system, HIV replicates, producing more copies of itself, each of which has to be assembled from a medley of viral and cellular components into an immature virus. This is the form that leaves the cell. The protein building blocks that make up the virus are then rearranged into the virus\u2019 mature form, which can infect other cells.<\/p>\n\n\n\n

Thanks to their refinement of cryo-electron microscopy techniques, Briggs and colleagues have obtained the first structure of the immature form of HIV at a high enough resolution to pinpoint exactly where each building block sits in the virus\u2019 protein lattice. When they did, they discovered that, like the puzzle forming an unexpected picture, those building blocks are not arranged in the pattern scientists had so far assumed.<\/p>\n\n\n\n

\u201cThe structure is definitely different from what we\u2019d expected,\u201d Briggs says. \u201cWe assumed that retroviruses like HIV and Mason-Pfizer Monkey Virus \u2013 which we had also studied before \u2013 would have similar structures, because they use such similar building blocks, but it turns out that their immature forms are surprisingly different from each other. At this point, we don\u2019t really know why.\u201d<\/p>\n\n\n\n

\"1411_hiv2\"
Surprisingly, the building blocks in immature HIV (centre) are arranged differently from those of immature Mason-Pfizer Monkey Virus (left). To form the mature virus, HIV\u2019s building blocks take on yet another arrangement (right). IMAGE: EMBL\/F.SCHUR<\/figcaption><\/figure><\/div>\n\n\n\n

With this structure in hand, scientists have a basis to probe further. They can use it to decide where to focus efforts for achieving the even greater detail needed to explore potential drug targets, for instance. It will also enable researchers to understand how mutations might influence how the virus assembles. And the techniques themselves can be applied to a variety of questions.<\/p>\n\n\n\n

\u201cThis approach offers so many possibilities,\u201d says Schur. \u201cYou can look at other viruses, of course, but also at complexes and proteins inside cells, with a whole new level of detail.\u201d<\/p>\n\n\n

EMBL-EBI has just launched EMPIAR<\/a>: a resource that lets researchers browse, download and reprocess thousands of raw, 2D electron microscopy images used to build 3D structures.
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In future, the EMBL scientists will use the approach to look at other viruses and at the vesicles that transport material inside cells. They also aim to push the techniques even further, to allow them to see other parts of the viral proteins that are currently beyond their reach, but which they suspect play an important role in HIV maturation.<\/p>\n\n\n\n

\u201cIn the long term, we\u2019d also like to investigate how drugs which are known to inhibit virus assembly and maturation actually work,\u201d Briggs concludes.<\/p>\n\n\n\n

Will there be more surprises along the way?<\/p>\n\n\n