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Virology. 2015 Nov;485:313-21. doi: 10.1016/j.virol.2015.08.006. Epub 2015 Aug 29.

Differential regulatory activities of viral protein X for anti-viral efficacy of nucleos(t)ide reverse transcriptase inhibitors in monocyte-derived macrophages and activated CD4(+) T cells.

Author information

1
Center for Drug Discovery, Department of Pediatrics, Emory University, Atlanta, GA, USA.
2
Center for Drug Discovery, Department of Pediatrics, Emory University, Atlanta, GA, USA; Veterans Affairs Medical Center, Atlanta, GA, USA.
3
Center for Drug Discovery, Department of Pediatrics, Emory University, Atlanta, GA, USA; College of Pharmacy, Kyung Hee University, Seoul, South Korea. Electronic address: baek.kim@emory.edu.

Abstract

Vpx encoded by HIV-2 and SIVsm enhances retroviral reverse transcription in macrophages in vitro by mediating the degradation of the host SAMHD1 protein that hydrolyzes dNTPs and by elevating cellular dNTP levels. Here we employed RT-SHIV constructs (SIV encoding HIV-1 RT) to investigate the contribution of Vpx to the potency of NRTIs, which compete against dNTPs, in monocyte-derived macrophages (MDMs) and activated CD4(+) T cells. Relative to HIV-1, both SIV and RT-SHIV exhibited reduced sensitivities to AZT, 3TC and TDF in MDMs but not in activated CD4(+) T cells. However, when SIV and RT-SHIV constructs not coding for Vpx were utilized, we observed greater sensitivities to all NRTIs tested using activated CD4(+) T cells relative to the Vpx-coding counterparts. This latter phenomenon was observed for AZT only when using MDMs. Our data suggest that Vpx in RT-SHIVs may underestimate the antiviral efficacy of NRTIs in a cell type dependent manner.

KEYWORDS:

Antiretrovirals; HIV-1; RT-SHIV; SAMHD1; SIV; Vpx

PMID:
26319213
PMCID:
PMC4619155
DOI:
10.1016/j.virol.2015.08.006
[Indexed for MEDLINE]
Free PMC Article

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