Exogenous HIV-1 Vpr disrupts IFN-α response by plasmacytoid dendritic cells (pDCs) and subsequent pDC/NK interplay

The HIV-1 accessory protein Vpr displays different activities potentially impacting viral replication, including the arrest of the cell cycle in the G 2 phase and the stimulation of apoptosis and DNA damage response pathways. Vpr also modulates cytokine production by infected cells, but this property remains partly characterized. Here, we investigated the effect of Vpr on the production of the proinflammatory cytokine tumor necrosis factor (TNF). We report that Vpr significantly increases TNF secretion by infected lymphocytes. De novo production of Vpr is required for this effect. Vpr mutants known to be defective for G

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Vpr Enhances Tumor Necrosis Factor Production by HIV-1-Infected T Cells

Roesch

Richard

Rua

et al. 2015

“…A number of NK cell abnormalities have been reported in HIV infection (9), including high activation status (2,10), increased turnover (16), differential expression of activating and inhibitory receptors (20), impaired interaction with dendritic cells (12), and loss of CD56 dim CD16 ϩ NK cells (23). CD56 dim CD16 ϩ NK cells represent the largest NK cell subset in peripheral blood in healthy individuals.…”

Section: Hiv-1 Infection Is Characterized By Loss Ofmentioning

confidence: 99%

HIV Infection Is Associated with a Preferential Decline in Less-Differentiated CD56^dimCD16⁺NK Cells

Hong

Eberhard

Keudel

et al. 2010

Self Cite

HIV-1 infection is characterized by loss of CD56dim CD16+ NK cells and increased terminal differentiation on various lymphocyte subsets. We identified a decrease of CD57− and CD57dim cells but not of CD57bright cells on CD56dim CD16+ NK cells in chronic HIV infection. Increasing CD57 expression was strongly associated with increasing frequencies of killer immunoglobulin-like receptors (KIRs) and granzyme B-expressing cells but decreasing percentages of cells expressing CD27+, HLA-DR+, Ki-67+, and CD107a. Our data indicate that HIV leads to a decline of less-differentiated cells and suggest that CD57 is a useful marker for terminal differentiation on NK cells.

“…Notably, there has been considerable heterogeneity in replication differences between wild-type (WT) and Vpr-deficient viruses and host responses to virus infection in MDMs, presumably due to donor and experimental variability between studies (12,29,30). Additionally, it has also been reported that Vpr expression in macrophages can both inhibit and induce type I interferon (IFN) responses (18,28,(31)(32)(33)(34).…”

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confidence: 99%

“…Exposure of target cells to type I IFN potently restricts HIV-1 replication in vitro (61)(62)(63)(64)(65)(66)(67)(68)(69). In addition, recent studies suggested that infection with ΔVpr virus induces type I IFN (18,28,(31)(32)(33)(34). Hence, we sought to determine if the induction of an early type I IFN response in HIV-1/ΔVpr infections of MDDCs accounts for the restricted virus replication and spread.…”

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confidence: 99%

Virion-Associated Vpr Alleviates a Postintegration Block to HIV-1 Infection of Dendritic Cells

Miller

Akiyama

Agosto

et al. 2017

Viral protein R (Vpr) is an HIV-1 accessory protein whose function remains poorly understood. In this report, we sought to determine the requirement of Vpr for facilitating HIV-1 infection of monocyte-derived dendritic cells (MDDCs), one of the first cell types to encounter virus in the peripheral mucosal tissues. In this report, we characterize a significant restriction of Vpr-deficient virus replication and spread in MDDCs alone and in cell-to-cell spread in MDDC-CD4 ϩ T cell cocultures. This restriction of HIV-1 replication in MDDCs was observed in a single round of virus replication and was rescued by the expression of Vpr in trans in the incoming virion. Interestingly, infections of MDDCs with viruses that encode Vpr mutants unable to interact with either the DCAF1/DDB1 E3 ubiquitin ligase complex or a host factor hypothesized to be targeted for degradation by Vpr also displayed a significant replication defect. While the extent of proviral integration in HIV-1-infected MDDCs was unaffected by the absence of Vpr, the transcriptional activity of the viral long terminal repeat (LTR) from Vpr-deficient proviruses was significantly reduced. Together, these results characterize a novel postintegration restriction of HIV-1 replication in MDDCs and show that the interaction of Vpr with the DCAF1/DDB1 E3 ubiquitin ligase complex and the yet-to-be-identified host factor might alleviate this restriction by inducing transcription from the viral LTR. Taken together, these findings identify a robust in vitro cell culture system that is amenable to addressing mechanisms underlying Vpr-mediated enhancement of HIV-1 replication.IMPORTANCE Despite decades of work, the function of the HIV-1 protein Vpr remains poorly understood, primarily due to the lack of an in vitro cell culture system that demonstrates a deficit in replication upon infection with viruses in the absence of Vpr. In this report, we describe a novel cell infection system that utilizes primary human dendritic cells, which display a robust decrease in viral replication upon infection with Vpr-deficient HIV-1. We show that this replication difference occurs in a single round of infection and is due to decreased transcriptional output from the integrated viral genome. Viral transcription could be rescued by virion-associated Vpr. Using mutational analysis, we show that domains of Vpr involved in binding to the DCAF1/DDB1/E3 ubiquitin ligase complex and prevention of cell cycle progression into mitosis are required for LTR-mediated viral expression, suggesting that the evolutionarily conserved G 2 cell cycle arrest function of Vpr is essential for HIV-1 replication.