Vpr Promotes Macrophage-Dependent HIV-1 Infection of CD4+ T Lymphocytes

Collins, David R.; Lubow, Jay; Lukic, Zana; Mashiba, Michael; Collins, Kathleen L.

doi:10.1371/journal.ppat.1005054

Cited by 31 publications

(38 citation statements)

References 50 publications

(88 reference statements)

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“…Previous work in this field suggests that Vpr likely regulates a complex network of host interactions that may vary depending on the cell type infected. We find that, unlike what has been previously observed in activated CD4 ϩ T cells and monocyte-derived macrophages (20,(22)(23)(24)(25)29), infection of MDDCs with ΔVpr viruses was significantly attenuated compared to WT HIV-1 infections (Fig. 1), similar to the findings reported previously by de Silva et al (41).…”

Section: Discussionsupporting

confidence: 89%

“…Although a number of previous studies have examined the requirement of Vpr for HIV-1 replication in various cell types, including primary CD4 ϩ T cells and monocytederived macrophages (MDMs), differences in virus replication have not been consistently observed (18,20,(22)(23)(24)(25)(26). Vpr expression is dispensable for infection in activated CD4 ϩ T cells in vitro (22)(23)(24)(25)27), presumably due to the well-characterized cytostatic and cytopathic functions of Vpr in cycling cells (12).…”

mentioning

confidence: 99%

“…Vpr expression is dispensable for infection in activated CD4 ϩ T cells in vitro (22)(23)(24)(25)27), presumably due to the well-characterized cytostatic and cytopathic functions of Vpr in cycling cells (12). In contrast, recent studies with MDMs suggest that Vpr is necessary for HIV-1 envelope (Env) expression, and the purported consequence of infection of MDMs with Vpr-deficient viruses was reported to be decreased viral production and reduced cell-to-cell spread to CD4 ϩ T cells (22,28). 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).…”

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confidence: 99%

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

Miller

Akiyama

Agosto

et al. 2017

J Virol

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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.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Miller

Akiyama

Agosto

et al. 2017

J Virol

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“…It was recently suggested that Vpr favors infection of macrophages by counteracting a restriction factor targeting Env expression and viral release (12). Vpr is also necessary for efficient cell-to-cell spread of HIV-1 from macrophages to CD4 + T lymphocytes (13). Vpr plays an important role in vivo.…”

mentioning

confidence: 99%

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

Lahouassa

Blondot

Chauveau

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Viruses often interfere with the DNA damage response to better replicate in their hosts. The human immunodeficiency virus 1 (HIV-1) viral protein R (Vpr) protein has been reported to modulate the activity of the DNA repair structure-specific endonuclease subunit (SLX4) complex and to promote cell cycle arrest. Vpr also interferes with the base-excision repair pathway by antagonizing the uracil DNA glycosylase (Ung2) enzyme. Using an unbiased quantitative proteomic screen, we report that Vpr down-regulates helicase-like transcription factor (HLTF), a DNA translocase involved in the repair of damaged replication forks. Vpr subverts the DDB1-cullin4-associatedfactor 1 (DCAF1) adaptor of the Cul4A ubiquitin ligase to trigger proteasomal degradation of HLTF. This event takes place rapidly after Vpr delivery to cells, before and independently of Vpr-mediated G2 arrest. HLTF is degraded in lymphocytic cells and macrophages infected with Vpr-expressing HIV-1. Our results reveal a previously unidentified strategy for HIV-1 to antagonize DNA repair in host cells.HIV | restriction factor | DNA repair | Vpr target | SILAC

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“…It was recently suggested that Vpr favors infection of macrophages by counteracting a restriction factor targeting Env expression and viral release (33). Vpr is also necessary for efficient cell-to-cell spread of HIV-1 from macrophages to CD4 ϩ T lymphocytes (34). Vpr plays an important role in vivo.…”

mentioning

confidence: 99%

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

Roesch

Richard

Rua

et al. 2015

J Virol

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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

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Vpr Promotes Macrophage-Dependent HIV-1 Infection of CD4+ T Lymphocytes

Cited by 31 publications

References 50 publications

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

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

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

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

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