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 the dNTP pool level, and the efficiency of proviral DNA synthesis 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 of MDMs with 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 between SAMHD1 level, dNTP levels, and HIV proviral DNA synthesis kinetics in MDMs.
Highlights
SAMHD1 is a host antiviral component that regulates cellular dNTP levels
We examine the kinetics of SAMHD1 degradation, the increase in the dNTP pool level, and the efficiency of proviral DNA synthesis in viral protein x (Vpx)؉ virus-like particle (VLP)-treated monocyte-derived macrophages (MDMs)
Our recent study revealed that the Vpx-mediated degradation of SAMHD1 causes an increase in the cellular dNTP pool size [11], which, in turn, allows HIV-1 reverse transcriptase (RT) to efficiently carry out reverse transcription of the viral RNA genome into double-stranded proviral DNA
Summary
SAMHD1 is a host antiviral component that regulates cellular dNTP levels. Results: We report a tight kinetic interplay between SAMHD1 level and the ability of HIV-1 to replicate in 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, leading to the enhancement of the HIV proviral DNA synthesis rate and HIV infection in MDMs. the pretreatment of MDMs with 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. The pretreatment of MDMs with 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. We simultaneously monitored these three molecular events after Vpx treatment in MDMs
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