期刊
OPEN BIOLOGY
卷 6, 期 7, 页码 -出版社
ROYAL SOC
DOI: 10.1098/rsob.160046
关键词
HIV-1; Vpr; NFAT; productive T-cell infection
资金
- Heinrich Pette Institute
- Leibniz Institute for Experimental Virology, Hamburg
- Helmholtz Zentrum Munich
- German Research Center for Environmental Health
- University Hospital Tuebingen
- Stiftung fur neurovirale Erkankungen
- Deutsche Forschungsgemeinschaft (DFG)
- Else Kroner-Fresenius Stiftung
- Ghent University [BOF11/GOA/013]
- HIVERA IRIFCURE
- Research Foundation-Flanders
The majority of T cells encountered by HIV-1 are non-activated and do not readily allow productive infection. HIV-1 Vpr is highly abundant in progeny virions, and induces signalling and HIV-1 LTR transcription. We hence hypothesized that Vpr might be a determinant of non-activated T-cell infection. Virion-delivered Vpr activated nuclear factor of activated T cells (NFAT) through Ca2+ influx and interference with the NFAT export kinase GSK3 beta. This leads to NFAT translocation and accumulation within the nucleus and was required for productive infection of unstimulated primary CD4(+) T cells. A mutagenesis approach revealed correlation of Vpr-mediated NFAT activation with its ability to enhance LTR transcription and mediate cell cycle arrest. Upon NFAT inhibition, Vpr did not augment resting T-cell infection, and showed reduced G2/M arrest and LTR transactivation. Altogether, Vpr renders unstimulated T cells more permissive for productive HIV-1 infection and stimulates activation of productively infected as well as virus-exposed T cells. Therefore, it could be involved in the establishment and reactivation of HIV-1 from viral reservoirs and might have an impact on the levels of immune activation, which are determinants of HIV-1 pathogenesis.
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