Vpx enhances innate immune responses independently of SAMHD1 during HIV-1 infection

Abstract

Background The genomes of HIV-2 and some SIV strains contain the accessory gene vpx, which carries out several functions during infection, including the downregulation of SAMHD1. Vpx is also commonly used in experiments to increase HIV-1 infection efficiency in myeloid cells, particularly in studies that investigate the activation of antiviral pathways. However, the potential effects of Vpx on cellular innate immune signaling is not completely understood. We investigated whether and how Vpx affects ISG responses in monocytic cell lines and MDMs during HIV-1 infection. Results HIV-1 infection at excessively high virus doses can induce ISG activation, although at the expense of high levels of cell death. At equal infection levels, the ISG response is potentiated by the presence of Vpx and requires the initiation of reverse transcription. The interaction of Vpx with the DCAF1 adaptor protein is important for the enhanced response, implicating Vpx-mediated degradation of a host factor. Cells lacking SAMHD1 show similarly augmented responses, suggesting an effect that is independent of SAMHD1 degradation. Overcoming SAMHD1 restriction in MDMs to reach equal infection levels with viruses containing and lacking Vpx reveals a novel function of Vpx in elevating innate immune responses. Conclusions Vpx likely has as yet undefined roles in infected cells. Our results demonstrate that Vpx enhances ISG responses in myeloid cell lines and primary cells independently of its ability to degrade SAMHD1. These findings have implications for innate immunity studies in myeloid cells that use Vpx delivery with HIV-1 infection.

Genetic Modification of Primary Human Myeloid Cells to Study Cell Migration, Activation, and Organelle Dynamics

“…2C). However, we cannot rule out that Vpx influences other aspects of myeloid cell biology unseen here, which may include alterations in interferon signaling, NF-κB activity, and gene silencing (Chougui et al, 2018;Cingoz, Arnow, Puig Torrents, & Bannert, 2021;Fink et al, 2022;Yurkovetskiy et al, 2018). Nevertheless, genetic modification of MDDCs through lentiviral-mediated gene delivery can be a useful tool for testing hypotheses related to cell activation, virus infection, and cell-cell communication.…”

Viral Particle-Mediated SAMHD1 Depletion Sensitizes Refractory Glioblastoma to DNA-Damaging Therapeutics by Impairing Homologous Recombination

“…However, optimization of the delivery tool to allow for penetration of the blood-brain barrier and to enhance anti-GBM specificity might be needed prior to advancing VLP(+Vpx) for clinical application. A recent study has shown that Vpx induces an innate immune response independent of SAMHD1 degradation [ 53 ], indicating a need for a careful evaluation of VLPs and Vpx activities prior to considering their use in clinical setting. On the promising side the tolerance of normal astrocytes to VLP(+Vpx) treatment shows a potentially lower effect on normal cells or tissue around the GBM.…”

HIV-1 infection causes depletion of monocytic cells through a non-canonical cell death pathway

“…We previously reported the occurrence of cell death in THP-1 cells inoculated with high virus inputs accompanied by the induction of an antiviral IFN-stimulated gene (ISG) response [22]. In this study, we further characterize the cellular and viral determinants of this virus-induced cell death in monocytic cells upon HIV infection.…”

“…Plasmids, virus production and infection. HIV-1-GFP was produced by transfection of the NL43-based viral plasmid pHIV-CMV-GFP SIVp6 (17)(18)(19)(20)(21)(22)(23)(24)(25)(26), which lacks env, nef and vpr genes, contains a 10 amino acid stretch from SIV p6 (for efficient Vpx packaging), and GFP expression is driven by a CMV promoter.…”