{"id":35176,"date":"2022-07-06T00:00:17","date_gmt":"2022-07-06T07:00:17","guid":{"rendered":"https:\/\/vermont.salk.edu\/?post_type=disclosure&p=35176"},"modified":"2024-01-30T14:23:51","modified_gmt":"2024-01-30T22:23:51","slug":"imaging-solves-mystery-of-how-large-hiv-protein-functions-to-form-infectious-virus","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/es\/news-release\/imaging-solves-mystery-of-how-large-hiv-protein-functions-to-form-infectious-virus\/","title":{"rendered":"Las im\u00e1genes desvelan el misterio de c\u00f3mo funciona una gran prote\u00edna del VIH para formar un virus infeccioso"},"content":{"rendered":"

LA JOLLA\u2014Understanding how HIV replicates within cells is key for developing new therapies that could help nearly 40 million people living with HIV globally. Now, a team of scientists from the Salk Institute and Rutgers University have for the first time determined the molecular structure of HIV Pol, a protein that plays a key role in the late stages of HIV replication, or the process through which the virus propagates itself and spreads through the body. Importantly, determining the molecule’s structure helps answer longstanding questions about how the protein breaks itself apart to advance the replication process. The discovery, published in Science Advances<\/em><\/a> on July 6, 2022, reveals a new vulnerability in the virus that could be targeted with drugs.<\/p>\n

\"Cartoon
Cartoon representation of the HIV-1 Pol structure.
Haga clic aqu\u00ed<\/a> para obtener una imagen en alta resoluci\u00f3n.
Credit: Francesc Xavier Ruiz from the Center for Advanced Biotechnology and Medicine at Rutgers<\/figcaption><\/figure>\n

\u201cStructure informs function, and the insights we gained from visualizing the molecular architecture of Pol give us a new understanding of the mechanism by which HIV replicates,\u201d says co-senior author Dmitry Lyumkis<\/a>, assistant professor in the Laboratory of Genetics and Hearst Foundation Developmental Chair at Salk.<\/p>\n

Scientists previously knew that HIV Pol, a polyprotein, breaks into three enzymes\u2014a protease, reverse transcriptase and integrase\u2014that work together to assemble the mature form of the virus. The protease plays a critical role in initiating this process by chopping up the molecule to separate the other components. However, it was previously unknown how the protease itself breaks free, first from the larger polyprotein HIV Gag-Pol and then from HIV Pol, to accomplish this task. The new paper suggests that the protease initiates the process by self-cleaving or cutting itself free from the rest of the molecule, aided by reverse transcriptase and, possibly, integrase.<\/p>\n

\u201cIt was known (but not understood) that there is a coupling between\u00a0these enzymes\u00a0before\u00a0HIV Pol breaks apart.\u00a0Visualizing the\u00a0HIV Pol structure explains\u00a0the\u00a0basis\u00a0for this complex mechanism,\u201d says co-senior author Eddy Arnold, board of governors professor and distinguished professor in the Center for Advanced Biotechnology and Medicine at Rutgers University.<\/p>\n

\u201cThe first challenge was producing a stable version of HIV Pol so the structure could be analyzed,\u00a0which had never previously been reported,\u201d says co-first author Jerry Joe Harrison, senior lecturer at the University of Ghana.<\/p>\n

\"From
From left: Dario Passos and Dmitry Lyumkis.
Haga clic aqu\u00ed<\/a> para obtener una imagen en alta resoluci\u00f3n.
Cr\u00e9dito: Instituto Salk<\/figcaption><\/figure>\n

\u201cThis was a key missing piece\u00a0of\u00a0the HIV structural puzzle,\u201d adds Arnold.<\/p>\n

The team used cryogenic electron microscopy, an imaging technique to which Lyumkis has made important contributions, to reveal the three-dimensional structure of the HIV pol protein molecule. This led to the discovery that Pol is a dimer, meaning it\u2019s formed by two proteins bound together. The finding was a surprise because other similar viral proteins are single-protein assemblies.<\/p>\n

The group showed that in this two-sided structure, the protease component of Pol is \u201cloosely tethered\u201d to the reverse transcriptase component in a binding configuration that keeps the protease slightly flexible.<\/p>\n

\u201cIt\u2019s holding the protease at arm\u2019s length, loosely, and we believe that gives the protease a little bit of movement, which in turn allows it to initiate the cutting of polyproteins that is a prerequisite for viral maturation,\u201d says co-first author Dario Passos, a former researcher in Lyumkis\u2019 lab at Salk. \u201cCurrent HIV treatments include multiple classes of inhibitors for all three enzymes, and the discovery also reveals a new vulnerability that could be targeted with drugs.\u201d<\/p>\n

The authors say the discovery opens the door for important follow-up research, including studies of the structure of the larger and more complex polyprotein Gag-Pol, also involved in viral assembly, as well as taking a closer look at the role of integrase in assembling the mature form of the HIV virus during replication.<\/p>\n

Other authors included Jessica F. Bruhn of Salk; Joseph Bauman, Lynda Tuberty and Francesc Xavier Ruiz of Rutgers; and Jeffrey DeStefano of the University of Maryland.<\/p>\n

The work was funded by the National Institutes of Health, International Institute of Education, Fulbright program, Margaret T. Morris Foundation and Hearst Foundations.<\/p>","protected":false},"featured_media":35184,"template":"","faculty":[320],"disease-research":[449,457,122,366,331],"class_list":["post-35176","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-dmitry-lyumkis","disease-research-biochemistry-and-biophysics","disease-research-hiv","disease-research-immune-system-biology","disease-research-infectious-disease","disease-research-protein-interactions"],"acf":[],"yoast_head":"\nImaging solves mystery of how large HIV protein functions to form infectious virus - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/es\/news-release\/imaging-solves-mystery-of-how-large-hiv-protein-functions-to-form-infectious-virus\/\" \/>\n<meta property=\"og:locale\" content=\"es_MX\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Imaging solves mystery of how large HIV protein functions to form infectious virus - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"LA JOLLA\u2014Understanding how HIV replicates within cells is key for developing new therapies that could help nearly 40 million people living with HIV globally. 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