Understanding the Structure of the HIV Protein May Lead to New Treatments
Scientists from Rutgers University and Salk Institute have determined the molecular structure of HIV Pol polyprotein, which plays a key role in helping the virus spread itself and systemically. This finding may stimulate new treatments for more than 40 million AIDS patients worldwide.
Their findings, published in Science Advances, could guide the development of drugs that bind to the protein and block its function.
'Drug molecules require a specific structure to specifically bind to their disease target,' said co-senior author Eddy Arnold, a Governing Council Professor and Distinguished Professor at Rutgers University's Center for Advanced Biotechnology and Medicine. 'They fit together like a complex puzzle. Knowing the structure of the target molecule can help find or make the right drug.'
Knowledge of the structure of the HIV Pol reveals how the HIV virus replicates itself. Previous studies have shown that the HIV Pol polyprotein breaks down into three enzymes, a protease, reverse transcriptase and integrase, that work together to assemble the mature viral form.
However, it was previously unknown how the protease itself broke free from the larger protein HIV Gag-Pol and then from HIV Pol. The new study shows that the protease initiates this process by cleaving itself or cutting itself from other parts of the molecule.
Jerry Joe Harrison, one of the first authors, said: 'The first challenge is to produce a stable natural transition HIV Pol so that its structure can be analyzed.' He developed a breakthrough formula to stabilize HIV Pol when he was a PhD at Rutgers University and is now a senior lecturer at the University of Ghana.
Once the researchers were able to create a stable version of HIV Pol, the Salk team used cryo-electron microscopy to reveal the three-dimensional structure of the HIV Pol protein molecule. This led to the discovery that Pol is a dimer, meaning that it is formed by two proteins bound together. The finding came as a surprise to the researchers because other similar viral proteins are single-protein assemblies.
Co-author Dmitry Lyumkis, an assistant professor at the Genetics Laboratory and chairman of Salkhurst Foundation development, said: “Structure determines function, and the insights we gained by visualizing the molecular structure of Pol have led to a new understanding of the mechanisms of HIV replication.”
'An unexpected finding is that the reverse transcriptase part of this multiprotein precursor is similar to its mature dimeric form,' Arnold said, who has studied HIV reverse transcriptase for 35 years and has successfully contributed to the development of some life-saving HIV treatments, which are widely used. Arnold said: 'HIV Pol polyprotein is one of the most important missing fragments in the HIV structural puzzle.'
The authors say this finding opens the door to important subsequent studies, including studies of the HIV Pol structure of the larger and more complex Gag-Pol polyprotein, also involving viral assembly, as well as further studies of the role of integrases in the assembly of mature forms of HIV viruses during replication.
'Current HIV treatment includes multiple inhibitors of these three enzymes, and this finding also reveals a new weakness that can be targeted with drugs,' said co-first author Dario Parsos, a former researcher at the Lyumkis laboratory at Salk University.
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