Abstract
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 GSK3β. 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.
Highlights
The HIV-1 accessory proteins Vif, Vpu, Nef and Vpr are dispensable for HIV-1 replication in most immortalized cell lines but essential for viral replication in vivo [1]
To clarify if Vpr is capable of enhancing productive infection of non-activated primary CD4þ T cells, we used NL4-3-based infectious HIV-1 expressing non-signalling murine heat-stable antigen (HSA) at the surface as a marker of infected cells upon replication
We infected cells with HIV-1 variants expressing either intact Vpr or Vpr mutated with a stop codon right after the start codon (Vpr Stop)
Summary
The HIV-1 accessory proteins Vif, Vpu, Nef and Vpr are dispensable for HIV-1 replication in most immortalized cell lines but essential for viral replication in vivo [1]. They all mediate viral immune evasion and exert effects enhancing viral loads, but Vpr is still enigmatic. It is a 12.7 kDa small protein and consists of three amphipathic helices. Until now, there is no link between the different Vpr effects and an essential in vivo function contributing to immune escape or high viral loads. Vpr mediated enhancement of CCR5 tropic HIV-1 replication in Tregs depleted this population, again associated with Vpr-induced G2/M arrest [8]
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