Tight interplay among SAMHD1 protein level, cellular dNTP levels, and HIV-1 proviral DNA synthesis kinetics in human primary monocyte-derived macrophages

Baek Kim, Laura A. Nguyen, Waaqo Daddacha, Joseph A. Hollenbaugh

Research output: Contribution to journalArticle

135 Scopus citations

Abstract

Recently, SAMHD1 has come under intense focus as a host anti-HIV factor. SAMHD1 is a dNTP triphosphohydrolase, which leads to the regulation of DNA metabolism in host cells. HIV-2/SIV (simian immunodeficiency virus) viral protein x (Vpx) has been shown to promote the degradation of SAMHD1. In this study, we examine the kinetics of SAMHD1 degradation, the increase in thedNTPpool level, and the efficiency of proviral DNAsynthesis in Vpx+virus-like particle (VLP)-treated monocyte- derived macrophages (MDMs). Our results indicate a very close temporal link with a reduction in SAMHD1 detected within the first few hours of Vpx+ VLP treatment. This loss of SAMHD1 is followed by a significant increase in cellular dNTP levels by 8 h after Vpx+ VLP addition, ultimately leading to the enhancement of the HIV proviral DNA synthesis rate and HIV infection in MDMs. Finally, the pretreatment ofMDMswith the Vpx+VLPs, which is a widely used protocol, displayed identical proviral DNA synthesis as compared with MDMs co-treated with Vpx+VLP and HIV vector. These findings further indicate that Vpx degradation of SAMHD1 is sufficiently rapid to enable appropriate progression of reverse transcription in MDMs, even when present at the time of infection. Overall, this study demonstrates a tight interplay betweenSAMHD1level, dNTP levels, and HIV proviral DNA synthesis kinetics in MDMs.

Original languageEnglish (US)
Pages (from-to)21570-21574
Number of pages5
JournalJournal of Biological Chemistry
Volume287
Issue number26
DOIs
StatePublished - Jun 22 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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