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Researchers from the Max Planck Institute of Biochemistry have discovered the mechanism behind an important step in the life cycle of HIV. Working together with teams at Heidelberg and Yale Universities, they found that the enigmatic “spacer peptide 2”, one of the virus components, plays a key role in converting immature HIV-1 particles into infectious particles. The results of the study were published in the journal Nature.
HIV-1 particles are released from infected cells in an immature, non-infectious form. The main building material for a virus particle is about 2000 copies of a long, rod-shaped protein called Gag. To become infectious, HIV has to undergo a maturation process. This involves the HIV-1 protease (a viral enzyme), that cuts up Gag into six smaller proteins including the capsid protein and the matrix protein. This causes a huge structural rearrangement of the virus components.
For many years, scientists have explored the structural changes of the virus capsid which encases the genome. In contrast, much less is known about the virus matrix - the outer protein shell directly beneath the lipid membrane that envelops the virus. Researchers led by John Briggs, director and structural biologist at the Max Planck Institute of Biochemistry, have now worked out how the matrix protein rearranges during maturation into the infectious particle.
They used the latest cryo-electron microscopes to image virus particles, and then used computational image analysis to derive very detailed 3D models of the viral proteins. Unexpectedly they found that the rearrangement of matrix is triggered by “spacer peptide 2” which sticks to matrix and causes it to pack together in a different way. Spacer peptide 2 is another one of the six components formed by cutting up Gag, but its function was unknown until now. Binding of spacer peptide 2 to matrix protein allows the virus to fuse with target cells more quickly. The work was performed together with partners from the University of Heidelberg and Yale University, USA.
John Briggs explains: “In our lab, we obtained the first structural data about the matrix in 2021, but we didn’t know what caused it to rearrange when the virus matures. In this new study we produced much more detailed 3D views of the matrix layer, that was key to understanding what is going on.”
James Stacey and Dominik Hrebík the two first authors of the study explain their findings. James says: “The virus matrix has a pocket in its mature form. We knew that something binds there, but we thought it was a lipid from the membrane. Now we can see that it is spacer peptide 2. We wonder whether this pocket could be a target for drug molecules in the future.” Dominik says: "Until now, the function of spacer peptide 2 was not known. Thanks to high-resolution cryo-electron microscopy, we have seen that this peptide, after its release, binds directly to the matrix proteins and links the proteins together in the mature virus.”
John Briggs summaries: “HIV-1 is probably the most studied virus, but there are still important steps in its replication we don’t yet understand.”
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Glossary
AIDS: Acquired Immune Deficiency Syndrome is a disease of the immune system caused by infection by HIV. Thanks to modern antiretroviral therapies that interfere with HIV replication, the onset of AIDS in HIV-infected individuals can be delayed or prevented.
Cryo-electron microscopy: cryos in Greek: cold; biological samples (e.g. purified proteins or cells) are shock-frozen in liquid ethane to prevent the formation of water crystals, enabling preservation in close-to-native conditions. The samples can then be visualized at high resolution with the help of electron microscopy.
Peptide: is a molecule composed of various amino acids linked together by peptide bonds. They have the same structure as proteins but are much smaller.
Polyprotein: is a large protein molecule that contains multiple functional proteins in a single chain. It is often produced by viruses and later cleaved into individual, active proteins. This cleavage into individual proteins is necessary for the formation of a virus that can replicate.
Proteolytic cleavage: Refers to proteins being cut up by proteases, enzymes that break the bonds between the basic building blocks of proteins, the amino acids.
Virus: A virus is an infectious particle consisting of a genome made by nucleic acids (DNA or RNA), surrounded by a protein coat (capsid), and depending on the type of virus, an additional envelope made of lipids.
Dr. John Briggs
Department Cell and Virus Structure
Max Planck Institute of Biochemistry
Am Klopferspitz 18
82152 Martinsried/Planegg
Germany
E-Mail: briggs@biochem.mpg.de
http://www.biochem.mpg.de/briggs
James C. V. Stacey, Dominik Hrebík, Elizabeth Nand, Snehith Dyavari Shetty, Kun Qu, Marius Boicu, Maria Anders-Össwein, Pradeep D. Uchil, Robert A. Dick, Walther Mothes, Hans-Georg Kräusslich, Barbara Müller & John A. G. Briggs: The conserved HIV-1 spacer peptide 2 triggers matrix lattice maturation, Nature, February 2025
DOI: 10.1038/s41586-025-08624-9
https://www.nature.com/articles/s41586-025-08624-9
?si=KQ5z2piK3Ik2c1c4 - Link zur Animation HIV Maturation
To become infectious, HIV must undergo a maturation process. In immature HIV, matrix proteins (red) ...
Illustration: Margot Riggi
MPI of Biochemistry
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To become infectious, HIV must undergo a maturation process. In immature HIV, matrix proteins (red) ...
Illustration: Margot Riggi
MPI of Biochemistry
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