Naturally occurring dipeptide from elite controllers with dual anti-HIV-1 mechanism
•WG-am is a naturally occurring dipeptide from elite controllers with anti-HIV activity.•WG-am is a new antiviral compound with two independent mechanisms of action against HIV.•WG-am binds to gp120 CD4 binding pocket and blocks the binding between HIV-1 and the host cell.•WG-am also exerts a post-e...
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Veröffentlicht in: | International journal of antimicrobial agents 2023-05, Vol.61 (5), p.106792-106792, Article 106792 |
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container_title | International journal of antimicrobial agents |
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creator | Ceña-Diez, Rafael Narayanan, Aswathy Ray, Shilpa van de Klundert, Maarten Rodriguez, Jimmy E Nilvebrant, Johan Nygren, Per-Åke Végvári, Ákos van Domselaar, Robert Sönnerborg, Anders |
description | •WG-am is a naturally occurring dipeptide from elite controllers with anti-HIV activity.•WG-am is a new antiviral compound with two independent mechanisms of action against HIV.•WG-am binds to gp120 CD4 binding pocket and blocks the binding between HIV-1 and the host cell.•WG-am also exerts a post-entry but pre-integration antiviral effect related to RT-activity.
Enhanced levels of a dipeptide, WG-am, have been reported among elite controllers – patients who spontaneously control their HIV-1 infection. This study aimed to evaluate anti-HIV-1 activity and mechanism of action of WG-am.
Drug sensitivity assays in TZM.bl cells, PBMCs and ACH-2 cells using WT and mutated HIV-1 strainswere performed to evaluate the antiviral mechanism of WG-am. Mass spectrometry-based proteomics and Real-time PCR analysis of reverse transcription steps were performed to unravel the second anti-HIV-1 mechanism of WG-am.
The data suggest that WG-am binds to the CD4 binding pocket of HIV-1 gp120 and blocks its binding to the host cell receptors. Additionally, the time course assay showed that WG-am also inhibited HIV-1 at 4–6 hours post-infection, suggesting a second antiviral mechanism. Drug sensitivity assays under acidic wash conditions confirmed the ability of WG-am to internalise into the host cell in an HIV independent manner. Proteomic studies showed a clustering of all samples treated with WG-am independent of the number of doses or presence or absence of HIV-1. Differentially expressed proteins due to the WG-am treatment indicated an effect on HIV-1 reverse transcription, which was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR).
Naturally occurring in HIV-1 elite controllers, WG-am stands out as a new kind of antiviral compound with two independent inhibitory mechanisms of action on HIV-1 replication. WG-am halts HIV-1 entry to the host cell by binding to HIV-1 gp120, thereby blocking the binding of HIV-1 to the host cell. WG-am also exerts a post-entry but pre-integration antiviral effect related to RT-activity. |
doi_str_mv | 10.1016/j.ijantimicag.2023.106792 |
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Enhanced levels of a dipeptide, WG-am, have been reported among elite controllers – patients who spontaneously control their HIV-1 infection. This study aimed to evaluate anti-HIV-1 activity and mechanism of action of WG-am.
Drug sensitivity assays in TZM.bl cells, PBMCs and ACH-2 cells using WT and mutated HIV-1 strainswere performed to evaluate the antiviral mechanism of WG-am. Mass spectrometry-based proteomics and Real-time PCR analysis of reverse transcription steps were performed to unravel the second anti-HIV-1 mechanism of WG-am.
The data suggest that WG-am binds to the CD4 binding pocket of HIV-1 gp120 and blocks its binding to the host cell receptors. Additionally, the time course assay showed that WG-am also inhibited HIV-1 at 4–6 hours post-infection, suggesting a second antiviral mechanism. Drug sensitivity assays under acidic wash conditions confirmed the ability of WG-am to internalise into the host cell in an HIV independent manner. Proteomic studies showed a clustering of all samples treated with WG-am independent of the number of doses or presence or absence of HIV-1. Differentially expressed proteins due to the WG-am treatment indicated an effect on HIV-1 reverse transcription, which was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR).
Naturally occurring in HIV-1 elite controllers, WG-am stands out as a new kind of antiviral compound with two independent inhibitory mechanisms of action on HIV-1 replication. WG-am halts HIV-1 entry to the host cell by binding to HIV-1 gp120, thereby blocking the binding of HIV-1 to the host cell. WG-am also exerts a post-entry but pre-integration antiviral effect related to RT-activity.</description><identifier>ISSN: 0924-8579</identifier><identifier>ISSN: 1872-7913</identifier><identifier>EISSN: 1872-7913</identifier><identifier>DOI: 10.1016/j.ijantimicag.2023.106792</identifier><identifier>PMID: 36931610</identifier><language>eng</language><publisher>Netherlands: Elsevier Ltd</publisher><subject>Antiviral ; Antiviral Agents ; Dipeptides ; Dual mechanism ; Elite Controllers ; Entry ; HIV ; HIV Infections - drug therapy ; HIV-1 ; Humans ; Medicin och hälsovetenskap ; Proteomics ; Retrotranscription ; Therapy ; Virus Replication</subject><ispartof>International journal of antimicrobial agents, 2023-05, Vol.61 (5), p.106792-106792, Article 106792</ispartof><rights>2023 The Author(s)</rights><rights>Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c604t-1f2bc25e9f0b77cb7fc02af9c640d74ef63552bc751a2b1293424110cff9019b3</citedby><cites>FETCH-LOGICAL-c604t-1f2bc25e9f0b77cb7fc02af9c640d74ef63552bc751a2b1293424110cff9019b3</cites><orcidid>0000-0002-9940-7366 ; 0000-0002-6104-6446 ; 0000-0003-4214-6991 ; 0000-0002-0626-1530 ; 0000-0001-6407-9481 ; 0000-0001-9987-395X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ijantimicag.2023.106792$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,315,553,781,785,886,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36931610$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-327401$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:152568776$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:236931610$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Ceña-Diez, Rafael</creatorcontrib><creatorcontrib>Narayanan, Aswathy</creatorcontrib><creatorcontrib>Ray, Shilpa</creatorcontrib><creatorcontrib>van de Klundert, Maarten</creatorcontrib><creatorcontrib>Rodriguez, Jimmy E</creatorcontrib><creatorcontrib>Nilvebrant, Johan</creatorcontrib><creatorcontrib>Nygren, Per-Åke</creatorcontrib><creatorcontrib>Végvári, Ákos</creatorcontrib><creatorcontrib>van Domselaar, Robert</creatorcontrib><creatorcontrib>Sönnerborg, Anders</creatorcontrib><title>Naturally occurring dipeptide from elite controllers with dual anti-HIV-1 mechanism</title><title>International journal of antimicrobial agents</title><addtitle>Int J Antimicrob Agents</addtitle><description>•WG-am is a naturally occurring dipeptide from elite controllers with anti-HIV activity.•WG-am is a new antiviral compound with two independent mechanisms of action against HIV.•WG-am binds to gp120 CD4 binding pocket and blocks the binding between HIV-1 and the host cell.•WG-am also exerts a post-entry but pre-integration antiviral effect related to RT-activity.
Enhanced levels of a dipeptide, WG-am, have been reported among elite controllers – patients who spontaneously control their HIV-1 infection. This study aimed to evaluate anti-HIV-1 activity and mechanism of action of WG-am.
Drug sensitivity assays in TZM.bl cells, PBMCs and ACH-2 cells using WT and mutated HIV-1 strainswere performed to evaluate the antiviral mechanism of WG-am. Mass spectrometry-based proteomics and Real-time PCR analysis of reverse transcription steps were performed to unravel the second anti-HIV-1 mechanism of WG-am.
The data suggest that WG-am binds to the CD4 binding pocket of HIV-1 gp120 and blocks its binding to the host cell receptors. Additionally, the time course assay showed that WG-am also inhibited HIV-1 at 4–6 hours post-infection, suggesting a second antiviral mechanism. Drug sensitivity assays under acidic wash conditions confirmed the ability of WG-am to internalise into the host cell in an HIV independent manner. Proteomic studies showed a clustering of all samples treated with WG-am independent of the number of doses or presence or absence of HIV-1. Differentially expressed proteins due to the WG-am treatment indicated an effect on HIV-1 reverse transcription, which was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR).
Naturally occurring in HIV-1 elite controllers, WG-am stands out as a new kind of antiviral compound with two independent inhibitory mechanisms of action on HIV-1 replication. WG-am halts HIV-1 entry to the host cell by binding to HIV-1 gp120, thereby blocking the binding of HIV-1 to the host cell. WG-am also exerts a post-entry but pre-integration antiviral effect related to RT-activity.</description><subject>Antiviral</subject><subject>Antiviral Agents</subject><subject>Dipeptides</subject><subject>Dual mechanism</subject><subject>Elite Controllers</subject><subject>Entry</subject><subject>HIV</subject><subject>HIV Infections - drug therapy</subject><subject>HIV-1</subject><subject>Humans</subject><subject>Medicin och hälsovetenskap</subject><subject>Proteomics</subject><subject>Retrotranscription</subject><subject>Therapy</subject><subject>Virus Replication</subject><issn>0924-8579</issn><issn>1872-7913</issn><issn>1872-7913</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNqdkktv1DAUhS0EokPhL6CwY5PBr9jjZTUUWqmCBdCt5TjXM546cbAdqv57MprpYwNCrGxdfefec-2D0DuClwQT8WG39DszFN97azZLiimb60Iq-gwtyErSWirCnqMFVpTXq0aqE_Qq5x3GpGG8eYlOmFCMCIIX6NsXU6ZkQrirorVTSn7YVJ0fYSy-g8ql2FcQfIHKxqGkGAKkXN36sq26yYRqb6O-uLyuSdWD3ZrB5_41euFMyPDmeJ6iH5_Ov68v6quvny_XZ1e1FZiXmjjaWtqAcriV0rbSWUyNU1Zw3EkOTrCmmRHZEENbQhXjlBOCrXMKE9WyU1Qf-uZbGKdWj8n3Jt3paLw-lm7mG2jOJVZ45tUf-THF7lF0L6T3D_UfWtLQRqykFH_1-dFfn-mYNvqmbDWjkmMy8-8P_Nz45wS56N5nCyGYAeKUNV1hLOjMskdbNsWcE7iH5gTrfVb0Tj_Jit5nRR-yMmvfHsdMbQ_dg_LJzusDAPMn_vKQdLYeBgudT2CL7qL_hzG_AaQC2Gs</recordid><startdate>20230501</startdate><enddate>20230501</enddate><creator>Ceña-Diez, Rafael</creator><creator>Narayanan, Aswathy</creator><creator>Ray, Shilpa</creator><creator>van de Klundert, Maarten</creator><creator>Rodriguez, Jimmy E</creator><creator>Nilvebrant, Johan</creator><creator>Nygren, Per-Åke</creator><creator>Végvári, Ákos</creator><creator>van Domselaar, Robert</creator><creator>Sönnerborg, Anders</creator><general>Elsevier Ltd</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>ADTPV</scope><scope>AFDQA</scope><scope>AOWAS</scope><scope>D8T</scope><scope>D8V</scope><scope>ZZAVC</scope><orcidid>https://orcid.org/0000-0002-9940-7366</orcidid><orcidid>https://orcid.org/0000-0002-6104-6446</orcidid><orcidid>https://orcid.org/0000-0003-4214-6991</orcidid><orcidid>https://orcid.org/0000-0002-0626-1530</orcidid><orcidid>https://orcid.org/0000-0001-6407-9481</orcidid><orcidid>https://orcid.org/0000-0001-9987-395X</orcidid></search><sort><creationdate>20230501</creationdate><title>Naturally occurring dipeptide from elite controllers with dual anti-HIV-1 mechanism</title><author>Ceña-Diez, Rafael ; Narayanan, Aswathy ; Ray, Shilpa ; van de Klundert, Maarten ; Rodriguez, Jimmy E ; Nilvebrant, Johan ; Nygren, Per-Åke ; Végvári, Ákos ; van Domselaar, Robert ; Sönnerborg, Anders</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c604t-1f2bc25e9f0b77cb7fc02af9c640d74ef63552bc751a2b1293424110cff9019b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Antiviral</topic><topic>Antiviral Agents</topic><topic>Dipeptides</topic><topic>Dual mechanism</topic><topic>Elite Controllers</topic><topic>Entry</topic><topic>HIV</topic><topic>HIV Infections - drug therapy</topic><topic>HIV-1</topic><topic>Humans</topic><topic>Medicin och hälsovetenskap</topic><topic>Proteomics</topic><topic>Retrotranscription</topic><topic>Therapy</topic><topic>Virus Replication</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ceña-Diez, Rafael</creatorcontrib><creatorcontrib>Narayanan, Aswathy</creatorcontrib><creatorcontrib>Ray, Shilpa</creatorcontrib><creatorcontrib>van de Klundert, Maarten</creatorcontrib><creatorcontrib>Rodriguez, Jimmy E</creatorcontrib><creatorcontrib>Nilvebrant, Johan</creatorcontrib><creatorcontrib>Nygren, Per-Åke</creatorcontrib><creatorcontrib>Végvári, Ákos</creatorcontrib><creatorcontrib>van Domselaar, Robert</creatorcontrib><creatorcontrib>Sönnerborg, Anders</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>SwePub</collection><collection>SWEPUB Kungliga Tekniska Högskolan full text</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SWEPUB Kungliga Tekniska Högskolan</collection><collection>SwePub Articles full text</collection><jtitle>International journal of antimicrobial agents</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ceña-Diez, Rafael</au><au>Narayanan, Aswathy</au><au>Ray, Shilpa</au><au>van de Klundert, Maarten</au><au>Rodriguez, Jimmy E</au><au>Nilvebrant, Johan</au><au>Nygren, Per-Åke</au><au>Végvári, Ákos</au><au>van Domselaar, Robert</au><au>Sönnerborg, Anders</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Naturally occurring dipeptide from elite controllers with dual anti-HIV-1 mechanism</atitle><jtitle>International journal of antimicrobial agents</jtitle><addtitle>Int J Antimicrob Agents</addtitle><date>2023-05-01</date><risdate>2023</risdate><volume>61</volume><issue>5</issue><spage>106792</spage><epage>106792</epage><pages>106792-106792</pages><artnum>106792</artnum><issn>0924-8579</issn><issn>1872-7913</issn><eissn>1872-7913</eissn><abstract>•WG-am is a naturally occurring dipeptide from elite controllers with anti-HIV activity.•WG-am is a new antiviral compound with two independent mechanisms of action against HIV.•WG-am binds to gp120 CD4 binding pocket and blocks the binding between HIV-1 and the host cell.•WG-am also exerts a post-entry but pre-integration antiviral effect related to RT-activity.
Enhanced levels of a dipeptide, WG-am, have been reported among elite controllers – patients who spontaneously control their HIV-1 infection. This study aimed to evaluate anti-HIV-1 activity and mechanism of action of WG-am.
Drug sensitivity assays in TZM.bl cells, PBMCs and ACH-2 cells using WT and mutated HIV-1 strainswere performed to evaluate the antiviral mechanism of WG-am. Mass spectrometry-based proteomics and Real-time PCR analysis of reverse transcription steps were performed to unravel the second anti-HIV-1 mechanism of WG-am.
The data suggest that WG-am binds to the CD4 binding pocket of HIV-1 gp120 and blocks its binding to the host cell receptors. Additionally, the time course assay showed that WG-am also inhibited HIV-1 at 4–6 hours post-infection, suggesting a second antiviral mechanism. Drug sensitivity assays under acidic wash conditions confirmed the ability of WG-am to internalise into the host cell in an HIV independent manner. Proteomic studies showed a clustering of all samples treated with WG-am independent of the number of doses or presence or absence of HIV-1. Differentially expressed proteins due to the WG-am treatment indicated an effect on HIV-1 reverse transcription, which was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR).
Naturally occurring in HIV-1 elite controllers, WG-am stands out as a new kind of antiviral compound with two independent inhibitory mechanisms of action on HIV-1 replication. WG-am halts HIV-1 entry to the host cell by binding to HIV-1 gp120, thereby blocking the binding of HIV-1 to the host cell. WG-am also exerts a post-entry but pre-integration antiviral effect related to RT-activity.</abstract><cop>Netherlands</cop><pub>Elsevier Ltd</pub><pmid>36931610</pmid><doi>10.1016/j.ijantimicag.2023.106792</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-9940-7366</orcidid><orcidid>https://orcid.org/0000-0002-6104-6446</orcidid><orcidid>https://orcid.org/0000-0003-4214-6991</orcidid><orcidid>https://orcid.org/0000-0002-0626-1530</orcidid><orcidid>https://orcid.org/0000-0001-6407-9481</orcidid><orcidid>https://orcid.org/0000-0001-9987-395X</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Antiviral Antiviral Agents Dipeptides Dual mechanism Elite Controllers Entry HIV HIV Infections - drug therapy HIV-1 Humans Medicin och hälsovetenskap Proteomics Retrotranscription Therapy Virus Replication |
title | Naturally occurring dipeptide from elite controllers with dual anti-HIV-1 mechanism |
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