The molecular structure of HIV Pol, a protein that plays a vital role in the late stages of HIV replication, or the process by which the virus propagates and spreads throughout the body, has been discovered by scientists.
Importantly, identifying the structure of the molecule helps to solve long-standing issues regarding how the protein separates itself to promote the replication process. The study shows a new viral weakness that might be exploited with medications.
“We obtained a new knowledge of the method by which HIV replicates by viewing the molecular architecture of Pol,” says co-senior author Dmitry Lyumkis, assistant professor in the Laboratory of Genetics and Hearst Foundation Developmental Chair at Salk.
Previously, scientists knew that HIV Pol, a polyprotein, splits into three enzymes — a protease, reverse transcriptase, and integrase — that work together to build the virus’s mature form. The protease enzyme is essential in starting this process by breaking up the molecule and separating the other components.
However, it was previously unknown how the protease, first from the bigger polyprotein HIV Gag-Pol and later from HIV Pol, accomplishes its activity.
According to the latest study, the protease commences the process by self-cleaving or cutting itself away from the remainder of the molecule, with the help of reverse transcriptase and potentially integrase.
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“It was previously recognised (but not understood) that there is a connection between these enzymes prior to HIV Pol breaking apart.” The visualisation of the HIV Pol structure shows the basis for this complicated process,” says co-senior author Eddy Arnold, board of governors professor and distinguished professor at Rutgers University’s Center for Advanced Biotechnology and Medicine.
“The initial issue was creating a stable form of HIV Pol so that the structure could be examined,” explains co-first author Jerry Joe Harrison, senior lecturer at the University of Ghana.
“This was a critical missing piece of the HIV structural puzzle,” Arnold says.
The researchers revealed the three-dimensional structure of the HIV pol protein molecule using cryogenic electron microscopy, an imaging technology to which Lyumkis has made significant contributions. This led to the finding that Pol is a dimer, which means it is made up of two proteins that are joined together. The discovery was surprising because other viral proteins are single-protein assemblages.
The researchers demonstrated that the protease component of Pol is “loosely linked” to the reverse transcriptase component in a binding conformation that allows the protease to be somewhat flexible.
“It’s holding the protease at arm’s length, loosely,” says co-first author Dario Passos, a former researcher in Lyumkis’ lab at Salk. “We believe that gives the protease a little bit of movement, which in turn allows it to initiate the cutting of polyproteins, which is a prerequisite for viral maturation.”
“Current HIV medicines include different types of inhibitors for all three enzymes, and the discovery also shows a new vulnerability that medications might target.”
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