Putting a Kink in HIV-1 Particle Infectivity: Rocaglamide Inhibits HIV-1 Replication by Altering Gag-Genomic RNA Interaction
Our examination of RNA helicases for effects on HIV-1 protein production and particle assembly identified Rocaglamide (RocA), a known modulator of eIF4A1 function, as an inhibitor of HIV-1 replication in primary CD4<sup>+</sup> T cells and three cell systems. HIV-1 attenuation by low-nM...
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2024-09-01
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| author | Paul Rosenfeld Gatikrushna Singh Amanda Paz Herrera Juan Ji Bradley Seufzer Xiao Heng Kathleen Boris-Lawrie Alan Cochrane |
| author_facet | Paul Rosenfeld Gatikrushna Singh Amanda Paz Herrera Juan Ji Bradley Seufzer Xiao Heng Kathleen Boris-Lawrie Alan Cochrane |
| author_sort | Paul Rosenfeld |
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| description | Our examination of RNA helicases for effects on HIV-1 protein production and particle assembly identified Rocaglamide (RocA), a known modulator of eIF4A1 function, as an inhibitor of HIV-1 replication in primary CD4<sup>+</sup> T cells and three cell systems. HIV-1 attenuation by low-nM RocA doses was associated with reduced viral particle formation without a marked decrease in Gag production. Rather, the co-localization of Gag and HIV-1 genomic RNA (gRNA) assemblies was impaired by RocA treatment in a reversible fashion. Ribonucleoprotein (RNP) immunoprecipitation studies recapitulated the loss of Gag-gRNA assemblies upon RocA treatment. Parallel biophysical studies determined that neither RocA nor eIF4A1 independently affected the ability of Gag to interact with viral RNA, but together, they distorted the structure of the HIV-1 RNP visualized by electron microscopy. Taken together, several lines of evidence indicate that RocA induces stable binding of eIF4A1 onto the viral RNA genome in a manner that interferes with the ordered assembly of Gag along Gag-gRNA assemblies required to generate infectious virions. |
| format | Article |
| id | doaj-art-c1097bdb587d4cc7a05a32e1f45331f9 |
| institution | OA Journals |
| issn | 1999-4915 |
| language | English |
| publishDate | 2024-09-01 |
| publisher | MDPI AG |
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| series | Viruses |
| spelling | doaj-art-c1097bdb587d4cc7a05a32e1f45331f92025-08-20T01:56:13ZengMDPI AGViruses1999-49152024-09-01169150610.3390/v16091506Putting a Kink in HIV-1 Particle Infectivity: Rocaglamide Inhibits HIV-1 Replication by Altering Gag-Genomic RNA InteractionPaul Rosenfeld0Gatikrushna Singh1Amanda Paz Herrera2Juan Ji3Bradley Seufzer4Xiao Heng5Kathleen Boris-Lawrie6Alan Cochrane7Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN 55108, USADepartment of Biochemistry, University of Missouri, Columbia, MO 65211, USADepartment of Biochemistry, University of Missouri, Columbia, MO 65211, USADepartment of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN 55108, USADepartment of Biochemistry, University of Missouri, Columbia, MO 65211, USADepartment of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN 55108, USAInstitute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, CanadaOur examination of RNA helicases for effects on HIV-1 protein production and particle assembly identified Rocaglamide (RocA), a known modulator of eIF4A1 function, as an inhibitor of HIV-1 replication in primary CD4<sup>+</sup> T cells and three cell systems. HIV-1 attenuation by low-nM RocA doses was associated with reduced viral particle formation without a marked decrease in Gag production. Rather, the co-localization of Gag and HIV-1 genomic RNA (gRNA) assemblies was impaired by RocA treatment in a reversible fashion. Ribonucleoprotein (RNP) immunoprecipitation studies recapitulated the loss of Gag-gRNA assemblies upon RocA treatment. Parallel biophysical studies determined that neither RocA nor eIF4A1 independently affected the ability of Gag to interact with viral RNA, but together, they distorted the structure of the HIV-1 RNP visualized by electron microscopy. Taken together, several lines of evidence indicate that RocA induces stable binding of eIF4A1 onto the viral RNA genome in a manner that interferes with the ordered assembly of Gag along Gag-gRNA assemblies required to generate infectious virions.https://www.mdpi.com/1999-4915/16/9/1506ribonucleoprotein assemblyeIF4A1guanosine-adenosine motifRNA structure |
| spellingShingle | Paul Rosenfeld Gatikrushna Singh Amanda Paz Herrera Juan Ji Bradley Seufzer Xiao Heng Kathleen Boris-Lawrie Alan Cochrane Putting a Kink in HIV-1 Particle Infectivity: Rocaglamide Inhibits HIV-1 Replication by Altering Gag-Genomic RNA Interaction Viruses ribonucleoprotein assembly eIF4A1 guanosine-adenosine motif RNA structure |
| title | Putting a Kink in HIV-1 Particle Infectivity: Rocaglamide Inhibits HIV-1 Replication by Altering Gag-Genomic RNA Interaction |
| title_full | Putting a Kink in HIV-1 Particle Infectivity: Rocaglamide Inhibits HIV-1 Replication by Altering Gag-Genomic RNA Interaction |
| title_fullStr | Putting a Kink in HIV-1 Particle Infectivity: Rocaglamide Inhibits HIV-1 Replication by Altering Gag-Genomic RNA Interaction |
| title_full_unstemmed | Putting a Kink in HIV-1 Particle Infectivity: Rocaglamide Inhibits HIV-1 Replication by Altering Gag-Genomic RNA Interaction |
| title_short | Putting a Kink in HIV-1 Particle Infectivity: Rocaglamide Inhibits HIV-1 Replication by Altering Gag-Genomic RNA Interaction |
| title_sort | putting a kink in hiv 1 particle infectivity rocaglamide inhibits hiv 1 replication by altering gag genomic rna interaction |
| topic | ribonucleoprotein assembly eIF4A1 guanosine-adenosine motif RNA structure |
| url | https://www.mdpi.com/1999-4915/16/9/1506 |
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