Host SAMHD1 protein restricts endogenous reverse transcription of HIV-1 in nondividing macrophages

• Type of Material: Article
• Authors: Bijan Mahboubi, Emory University; Christina Gavegnano, Emory University; Dong-Hyun Kim, Kyung-Hee University; Raymond Schinazi, Emory University; Baek Kim, Emory University
• Language: English
• Date: 2018-10-13
• Publisher: BMC (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12977-018-0452-z
• Title of Journal or Parent Work: Retrovirology
• ISSN: 1742-4690
• Volume: 15
• Issue: 1
• Start Page: 69
• End Page: 69
• Grant/Funding Information: This work was supported by NIH AI136581 (B.K.), GM104198 (B.K.), and MH1166950 (R.F.S.).
• Keywords: Reverse transcription; HIV-1; INFECTION; Virology; TYPE-1; Endogenous reverse transcription; SAMHD1; INTEGRATION; DNA; Science & Technology; HIV-2; Macrophages; MONOCYTE-DERIVED MACROPHAGES; REPLICATION; Life Sciences & Biomedicine; DNTPASE ACTIVITY; HUMAN-IMMUNODEFICIENCY-VIRUS; dNTPs; Vpx; CELLS; KINETICS
• Research Categories: Health Sciences, Public Health

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.