Host SAMHD1 protein restricts endogenous reverse transcription of HIV-1 in nondividing macrophages
Abstract Background SAM domain and HD domain containing protein 1 (SAMHD1) is a host anti-HIV-1 restriction factor known to suppress viral reverse transcription in nondividing myeloid cells by its dNTP triphosphorylase activity that depletes cellular dNTPs. However, HIV-2 and some SIV strains rapidl...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-10-01
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| Series: | Retrovirology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12977-018-0452-z |
| _version_ | 1818451337581428736 |
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| author | Bijan Mahboubi Christina Gavegnano Dong-Hyun Kim Raymond F. Schinazi Baek Kim |
| author_facet | Bijan Mahboubi Christina Gavegnano Dong-Hyun Kim Raymond F. Schinazi Baek Kim |
| author_sort | Bijan Mahboubi |
| collection | DOAJ |
| description | Abstract Background SAM domain and HD domain containing protein 1 (SAMHD1) is a host anti-HIV-1 restriction factor known to suppress viral reverse transcription in nondividing myeloid cells by its dNTP triphosphorylase activity that depletes cellular dNTPs. However, HIV-2 and some SIV strains rapidly replicate in macrophages due to their accessory protein, viral protein X (Vpx), which proteosomally degrades SAMHD1 and elevates dNTP levels. Endogenous reverse transcription (ERT) of retroviruses is the extra-cellular reverse transcription step that partially synthesizes proviral DNAs within cell-free viral particles before the viruses infect new cells. ERT activity utilizes dNTPs co-packaged during budding from the virus-producing cells, and high ERT activity is known to enhance HIV-1 infectivity in nondividing cells. Here, since Vpx elevates cellular dNTP levels in macrophages, we hypothesize that HIV-2 should contain higher ERT activity than HIV-1 in macrophages, and that the Vpx-mediated dNTP elevation should enhance both ERT activity and infectivity of HIV-1 particles produced in macrophages. Results Here, we demonstrate that HIV-2 produced from human primary monocyte derived macrophages displays higher ERT activity than HIV-1 produced from macrophages. Also, HIV-1 particles produced from macrophages treated with virus like particles (VLPs) containing Vpx, Vpx (+), displayed large increases of ERT activity with the enhanced copy numbers of early, middle and late reverse transcription products within the viral particles, compared to the viruses produced from macrophages treated with Vpx (−) VLPs. Furthermore, upon the infection with an equal p24 amount to fresh macrophages, the viruses produced from the Vpx (+) VLP treated macrophages demonstrated higher infectivity than the viruses from the Vpx (−) VLP treated macrophages. Conclusions This finding identifies the viral ERT step as an additional step of HIV-1 replication cycle that SAMHD1 restricts in nondividing myeloid target cells. |
| first_indexed | 2024-12-14T21:05:36Z |
| format | Article |
| id | doaj.art-965a9dba4365407f8bb6edd50cf7b4e4 |
| institution | Directory Open Access Journal |
| issn | 1742-4690 |
| language | English |
| last_indexed | 2024-12-14T21:05:36Z |
| publishDate | 2018-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Retrovirology |
| spelling | doaj.art-965a9dba4365407f8bb6edd50cf7b4e42022-12-21T22:47:29ZengBMCRetrovirology1742-46902018-10-0115111110.1186/s12977-018-0452-zHost SAMHD1 protein restricts endogenous reverse transcription of HIV-1 in nondividing macrophagesBijan Mahboubi0Christina Gavegnano1Dong-Hyun Kim2Raymond F. Schinazi3Baek Kim4Center for Drug Discovery, Department of Pediatrics, School of Medicine, Emory UniversityCenter for Drug Discovery, Department of Pediatrics, School of Medicine, Emory UniversitySchool of Pharmacy, Kyung-Hee UniversityCenter for Drug Discovery, Department of Pediatrics, School of Medicine, Emory UniversityCenter for Drug Discovery, Department of Pediatrics, School of Medicine, Emory UniversityAbstract Background SAM domain and HD domain containing protein 1 (SAMHD1) is a host anti-HIV-1 restriction factor known to suppress viral reverse transcription in nondividing myeloid cells by its dNTP triphosphorylase activity that depletes cellular dNTPs. However, HIV-2 and some SIV strains rapidly replicate in macrophages due to their accessory protein, viral protein X (Vpx), which proteosomally degrades SAMHD1 and elevates dNTP levels. Endogenous reverse transcription (ERT) of retroviruses is the extra-cellular reverse transcription step that partially synthesizes proviral DNAs within cell-free viral particles before the viruses infect new cells. ERT activity utilizes dNTPs co-packaged during budding from the virus-producing cells, and high ERT activity is known to enhance HIV-1 infectivity in nondividing cells. Here, since Vpx elevates cellular dNTP levels in macrophages, we hypothesize that HIV-2 should contain higher ERT activity than HIV-1 in macrophages, and that the Vpx-mediated dNTP elevation should enhance both ERT activity and infectivity of HIV-1 particles produced in macrophages. Results Here, we demonstrate that HIV-2 produced from human primary monocyte derived macrophages displays higher ERT activity than HIV-1 produced from macrophages. Also, HIV-1 particles produced from macrophages treated with virus like particles (VLPs) containing Vpx, Vpx (+), displayed large increases of ERT activity with the enhanced copy numbers of early, middle and late reverse transcription products within the viral particles, compared to the viruses produced from macrophages treated with Vpx (−) VLPs. Furthermore, upon the infection with an equal p24 amount to fresh macrophages, the viruses produced from the Vpx (+) VLP treated macrophages demonstrated higher infectivity than the viruses from the Vpx (−) VLP treated macrophages. Conclusions This finding identifies the viral ERT step as an additional step of HIV-1 replication cycle that SAMHD1 restricts in nondividing myeloid target cells.http://link.springer.com/article/10.1186/s12977-018-0452-zHIV-1HIV-2Reverse transcriptionEndogenous reverse transcriptionSAMHD1Vpx |
| spellingShingle | Bijan Mahboubi Christina Gavegnano Dong-Hyun Kim Raymond F. Schinazi Baek Kim Host SAMHD1 protein restricts endogenous reverse transcription of HIV-1 in nondividing macrophages Retrovirology HIV-1 HIV-2 Reverse transcription Endogenous reverse transcription SAMHD1 Vpx |
| title | Host SAMHD1 protein restricts endogenous reverse transcription of HIV-1 in nondividing macrophages |
| title_full | Host SAMHD1 protein restricts endogenous reverse transcription of HIV-1 in nondividing macrophages |
| title_fullStr | Host SAMHD1 protein restricts endogenous reverse transcription of HIV-1 in nondividing macrophages |
| title_full_unstemmed | Host SAMHD1 protein restricts endogenous reverse transcription of HIV-1 in nondividing macrophages |
| title_short | Host SAMHD1 protein restricts endogenous reverse transcription of HIV-1 in nondividing macrophages |
| title_sort | host samhd1 protein restricts endogenous reverse transcription of hiv 1 in nondividing macrophages |
| topic | HIV-1 HIV-2 Reverse transcription Endogenous reverse transcription SAMHD1 Vpx |
| url | http://link.springer.com/article/10.1186/s12977-018-0452-z |
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