A cellular trafficking signal in the SIV envelope protein cytoplasmic domain is strongly selected for in pathogenic infection.
The HIV/SIV envelope glycoprotein (Env) cytoplasmic domain contains a highly conserved Tyr-based trafficking signal that mediates both clathrin-dependent endocytosis and polarized sorting. Despite extensive analysis, the role of these functions in viral infection and pathogenesis is unclear. An SIV...
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| Language: | English |
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Public Library of Science (PLoS)
2022-06-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1010507&type=printable |
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| author | Scott P Lawrence Samra E Elser Workineh Torben Robert V Blair Bapi Pahar Pyone P Aye Faith Schiro Dawn Szeltner Lara A Doyle-Meyers Beth S Haggarty Andrea P O Jordan Josephine Romano George J Leslie Xavier Alvarez David H O'Connor Roger W Wiseman Christine M Fennessey Yuan Li Michael Piatak Jeffrey D Lifson Celia C LaBranche Andrew A Lackner Brandon F Keele Nicholas J Maness Mark Marsh James A Hoxie |
| author_facet | Scott P Lawrence Samra E Elser Workineh Torben Robert V Blair Bapi Pahar Pyone P Aye Faith Schiro Dawn Szeltner Lara A Doyle-Meyers Beth S Haggarty Andrea P O Jordan Josephine Romano George J Leslie Xavier Alvarez David H O'Connor Roger W Wiseman Christine M Fennessey Yuan Li Michael Piatak Jeffrey D Lifson Celia C LaBranche Andrew A Lackner Brandon F Keele Nicholas J Maness Mark Marsh James A Hoxie |
| author_sort | Scott P Lawrence |
| collection | DOAJ |
| description | The HIV/SIV envelope glycoprotein (Env) cytoplasmic domain contains a highly conserved Tyr-based trafficking signal that mediates both clathrin-dependent endocytosis and polarized sorting. Despite extensive analysis, the role of these functions in viral infection and pathogenesis is unclear. An SIV molecular clone (SIVmac239) in which this signal is inactivated by deletion of Gly-720 and Tyr-721 (SIVmac239ΔGY), replicates acutely to high levels in pigtail macaques (PTM) but is rapidly controlled. However, we previously reported that rhesus macaques and PTM can progress to AIDS following SIVmac239ΔGY infection in association with novel amino acid changes in the Env cytoplasmic domain. These included an R722G flanking the ΔGY deletion and a nine nucleotide deletion encoding amino acids 734-736 (ΔQTH) that overlaps the rev and tat open reading frames. We show that molecular clones containing these mutations reconstitute signals for both endocytosis and polarized sorting. In one PTM, a novel genotype was selected that generated a new signal for polarized sorting but not endocytosis. This genotype, together with the ΔGY mutation, was conserved in association with high viral loads for several months when introduced into naïve PTMs. For the first time, our findings reveal strong selection pressure for Env endocytosis and particularly for polarized sorting during pathogenic SIV infection in vivo. |
| format | Article |
| id | doaj-art-d548a853acc4469fa6a4e1326a82b9a7 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2022-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-d548a853acc4469fa6a4e1326a82b9a72025-08-20T03:25:46ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742022-06-01186e101050710.1371/journal.ppat.1010507A cellular trafficking signal in the SIV envelope protein cytoplasmic domain is strongly selected for in pathogenic infection.Scott P LawrenceSamra E ElserWorkineh TorbenRobert V BlairBapi PaharPyone P AyeFaith SchiroDawn SzeltnerLara A Doyle-MeyersBeth S HaggartyAndrea P O JordanJosephine RomanoGeorge J LeslieXavier AlvarezDavid H O'ConnorRoger W WisemanChristine M FennesseyYuan LiMichael PiatakJeffrey D LifsonCelia C LaBrancheAndrew A LacknerBrandon F KeeleNicholas J ManessMark MarshJames A HoxieThe HIV/SIV envelope glycoprotein (Env) cytoplasmic domain contains a highly conserved Tyr-based trafficking signal that mediates both clathrin-dependent endocytosis and polarized sorting. Despite extensive analysis, the role of these functions in viral infection and pathogenesis is unclear. An SIV molecular clone (SIVmac239) in which this signal is inactivated by deletion of Gly-720 and Tyr-721 (SIVmac239ΔGY), replicates acutely to high levels in pigtail macaques (PTM) but is rapidly controlled. However, we previously reported that rhesus macaques and PTM can progress to AIDS following SIVmac239ΔGY infection in association with novel amino acid changes in the Env cytoplasmic domain. These included an R722G flanking the ΔGY deletion and a nine nucleotide deletion encoding amino acids 734-736 (ΔQTH) that overlaps the rev and tat open reading frames. We show that molecular clones containing these mutations reconstitute signals for both endocytosis and polarized sorting. In one PTM, a novel genotype was selected that generated a new signal for polarized sorting but not endocytosis. This genotype, together with the ΔGY mutation, was conserved in association with high viral loads for several months when introduced into naïve PTMs. For the first time, our findings reveal strong selection pressure for Env endocytosis and particularly for polarized sorting during pathogenic SIV infection in vivo.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1010507&type=printable |
| spellingShingle | Scott P Lawrence Samra E Elser Workineh Torben Robert V Blair Bapi Pahar Pyone P Aye Faith Schiro Dawn Szeltner Lara A Doyle-Meyers Beth S Haggarty Andrea P O Jordan Josephine Romano George J Leslie Xavier Alvarez David H O'Connor Roger W Wiseman Christine M Fennessey Yuan Li Michael Piatak Jeffrey D Lifson Celia C LaBranche Andrew A Lackner Brandon F Keele Nicholas J Maness Mark Marsh James A Hoxie A cellular trafficking signal in the SIV envelope protein cytoplasmic domain is strongly selected for in pathogenic infection. PLoS Pathogens |
| title | A cellular trafficking signal in the SIV envelope protein cytoplasmic domain is strongly selected for in pathogenic infection. |
| title_full | A cellular trafficking signal in the SIV envelope protein cytoplasmic domain is strongly selected for in pathogenic infection. |
| title_fullStr | A cellular trafficking signal in the SIV envelope protein cytoplasmic domain is strongly selected for in pathogenic infection. |
| title_full_unstemmed | A cellular trafficking signal in the SIV envelope protein cytoplasmic domain is strongly selected for in pathogenic infection. |
| title_short | A cellular trafficking signal in the SIV envelope protein cytoplasmic domain is strongly selected for in pathogenic infection. |
| title_sort | cellular trafficking signal in the siv envelope protein cytoplasmic domain is strongly selected for in pathogenic infection |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1010507&type=printable |
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