The human antiviral factor TRIM11 is under the regulation of HIV-1 Vpr.
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ABSTRACT:
SUBMITTER: Yuan T
PROVIDER: S-EPMC4126725 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
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Project description:HIV-1 accessory protein, Vpr, is required for efficient HIV-1 infection of macrophages. Here we show that Vpr reprograms macrophage gene expression by altering the activity of master transcriptional regulator, PU.1, which is responsible for regulating the expression of host immune response genes and is necessary for normal hematopoiesis. In HIV-infected primary macrophages, Vpr-dependent changes in PU.1 levels result in suppression of known anti-viral targets of Vpr including IFITM3 and MRC1. Moreover, we find that PU.1 and its co-factor TET2 are co-recruited to DCAF1 by Vpr and targeted for accelerated degradation. Downmodulation of PU.1 is a highly conserved function of Vpr that is maintained across primate lentiviruses including HIV-2 and several SIVs. In contrast, this activity is not shared by the evolutionarily related accessory protein Vpx. Our findings demonstrate how Vpr dramatically enhances HIV spread in macrophages by targeting a myeloid-specific transcription factor needed for expression of multiple viral restriction factors.
2024-04-30 | GSE220574 | GEO
Project description:The human immunodeficiency virus type 1 (HIV-1) accessory protein Vpr enhances viral replication in both macrophages and, to a lesser extent, cycling T cells. Virion-packaged Vpr is released in target cells shortly after entry, suggesting it is required in the early phase of infection. Previously, we described REAF (RNA-associated early-stage antiviral factor; RPRD2), a constitutively expressed protein that potently restricts HIV replication at or during reverse transcription. Here, we show that a virus without an intact vpr gene is more highly restricted by REAF and, using delivery by virus-like particles (VLPs), that Vpr alone is sufficient for REAF degradation in primary macrophages. REAF is more highly expressed in macrophages than in cycling T cells, and we detected, by coimmunoprecipitation assay, an interaction between Vpr protein and endogenous REAF. Vpr acts quickly during the early phase of replication and induces the degradation of REAF within 30 min of viral entry. Using Vpr F34I and Q65R viral mutants, we show that nuclear localization and interaction with cullin 4A-DBB1 (DCAF1) E3 ubiquitin ligase are required for REAF degradation by Vpr. In response to infection, cells upregulate REAF levels. This response is curtailed in the presence of Vpr. These findings support the hypothesis that Vpr induces the degradation of a factor, REAF, that impedes HIV infection in macrophages.IMPORTANCE For at least 30?years, it has been known that HIV-1 Vpr, a protein carried in the virion, is important for efficient infection of primary macrophages. Vpr is also a determinant of the pathogenic effects of HIV-1 in vivo A number of cellular proteins that interact with Vpr have been identified. So far, it has not been possible to associate these proteins with altered viral replication in macrophages or to explain why Vpr is carried in the virus particle. Here, we show that Vpr mitigates the antiviral effects of REAF, a protein highly expressed in primary macrophages and one that inhibits virus replication during reverse transcription. REAF is degraded by Vpr within 30 min of virus entry in a manner dependent on the nuclear localization of Vpr and its interaction with the cell's protein degradation machinery.
| S-EPMC6997760 | biostudies-literature
Project description:The innate immune response is a host defense mechanism against infection by viruses and bacteria. Type I interferons (IFN?/?) play a crucial role in innate immunity. If not tightly regulated under normal conditions and during immune responses, IFN production can become aberrant, leading to inflammatory and autoimmune diseases. In this study, we identified TRIM11 (tripartite motif containing 11) as a novel negative regulator of IFN? production. Ectopic expression of TRIM11 decreased IFN? promoter activity induced by poly (I:C) stimulation or overexpression of RIG-I (retinoic acid-inducible gene-I) signaling cascade components RIG-IN (constitutively active form of RIG-I), MAVS (mitochondrial antiviral signaling protein), or TBK1 (TANK-binding kinase-1). Conversely, TRIM11 knockdown enhanced IFN? promoter activity induced by these stimuli. Moreover, TRIM11 overexpression inhibited the phosphorylation and dimerization of IRF3 and expression of IFN? mRNA. By contrast, TRIM11 knockdown increased the IRF3 phosphorylation and IFN? mRNA expression. We also found that TRIM11 and TBK1, a key kinase that phosphorylates IRF3 in the RIG-I pathway, interacted with each other through CC and CC2 domain, respectively. This interaction was enhanced in the presence of the TBK1 adaptor proteins, NAP1 (NF-?B activating kinase-associated protein-1), SINTBAD (similar to NAP1 TBK1 adaptor) or TANK (TRAF family member-associated NF-?B activator). Consistent with its inhibitory role in RIG-I-mediated IFN? signaling, TRIM11 overexpression enhanced viral infectivity, whereas TRIM11 knockdown produced the opposite effect. Collectively, our results suggest that TRIM11 inhibits RIG-I-mediated IFN? production by targeting the TBK1 signaling complex.
| S-EPMC3652858 | biostudies-literature
Project description:The HIV-1 accessory protein Vpr is required for efficient viral infection of macrophages and promotion of viral replication in T cells. Vpr's biological activities are closely linked to the interaction with human DCAF1, a cellular substrate receptor of the Cullin4-RING E3 ubiquitin ligase (CRL4) of the host ubiquitin-proteasome-mediated protein degradation pathway. The molecular details of how Vpr usurps the protein degradation pathway have not been delineated. Here we present the crystal structure of the DDB1-DCAF1-HIV-1-Vpr-uracil-DNA glycosylase (UNG2) complex. The structure reveals how Vpr engages with DCAF1, creating a binding interface for UNG2 recruitment in a manner distinct from the recruitment of SAMHD1 by Vpx proteins. Vpr and Vpx use similar N-terminal and helical regions to bind the substrate receptor, whereas different regions target the specific cellular substrates. Furthermore, Vpr uses molecular mimicry of DNA by a variable loop for specific recruitment of the UNG2 substrate.
| S-EPMC5385928 | biostudies-literature
Project description:UnlabelledThe HIV-1 accessory protein Vpr displays different activities potentially impacting viral replication, including the arrest of the cell cycle in the G2 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 G2 cell cycle arrest induce lower levels of TNF secretion, suggesting a link between these two functions. Silencing experiments and the use of chemical inhibitors further implicated the cellular proteins DDB1 and TAK1 in this activity of Vpr. TNF secreted by HIV-1-infected cells triggers NF-?B activity in bystander cells and allows viral reactivation in a model of latently infected cells. Thus, the stimulation of the proinflammatory pathway by Vpr may impact HIV-1 replication in vivo.ImportanceThe role of the HIV-1 accessory protein Vpr remains only partially characterized. This protein is important for viral pathogenesis in infected individuals but is dispensable for viral replication in most cell culture systems. Some of the functions described for Vpr remain controversial. In particular, it remains unclear whether Vpr promotes or instead prevents proinflammatory and antiviral immune responses. In this report, we show that Vpr promotes the release of TNF, a proinflammatory cytokine associated with rapid disease progression. Using Vpr mutants or inhibiting selected cellular genes, we show that the cellular proteins DDB1 and TAK1 are involved in the release of TNF by HIV-infected cells. This report provides novel insights into how Vpr manipulates TNF production and helps clarify the role of Vpr in innate immune responses and inflammation.
| S-EPMC4645299 | biostudies-literature
Project description:HIV-1 Vpr is necessary for maximal HIV infection and spread in macrophages. Evolutionary conservation of Vpr suggests an important yet poorly understood role for macrophages in HIV pathogenesis. Vpr counteracts a previously unknown macrophage-specific restriction factor that targets and reduces the expression of HIV Env. Here, we report that the macrophage mannose receptor (MR), is a restriction factor targeting Env in primary human monocyte-derived macrophages. Vpr acts synergistically with HIV Nef to target distinct stages of the MR biosynthetic pathway and dramatically reduce MR expression. Silencing MR or deleting mannose residues on Env rescues Env expression in HIV-1-infected macrophages lacking Vpr. However, we also show that disrupting interactions between Env and MR reduces initial infection of macrophages by cell-free virus. Together these results reveal a Vpr-Nef-Env axis that hijacks a host mannose-MR response system to facilitate infection while evading MR's normal role, which is to trap and destroy mannose-expressing pathogens.
| S-EPMC7051176 | biostudies-literature
Project description:Macrophages act as reservoirs of human immunodeficiency virus type 1 (HIV-1) and play an important role in its transmission to other cells. HIV-1 Vpr is a multi-functional protein involved in HIV-1 replication and pathogenesis; however, its exact role in HIV-1-infected human macrophages remains poorly understood. In this study, we used a microarray approach to explore the effects of HIV-1 Vpr on the transcriptional profile of human monocyte-derived macrophages (MDMs). More than 500 genes, mainly those involved in the innate immune response, the type I interferon pathway, cytokine production, and signal transduction, were differentially regulated (fold change >2.0) after infection with a recombinant adenovirus expressing HIV-1 Vpr protein. The differential expression profiles of select interferon-stimulated genes (ISGs) and genes involved in the innate immune response, including STAT1, IRF7, MX1, MX2, ISG15, ISG20, IFIT1, IFIT2, IFIT3, IFI27, IFI44L, APOBEC3A, DDX58 (RIG-I), TNFSF10 (TRAIL), and RSAD2 (viperin) were confirmed by real-time quantitative PCR and were consistent with the microarray data. In addition, at the post-translational level, HIV-1 Vpr induced the phosphorylation of STAT1 at tyrosine 701 in human MDMs. These results demonstrate that HIV-1 Vpr leads to the induction of ISGs and expand the current understanding of the function of Vpr and its role in HIV-1 immune pathogenesis.
| S-EPMC4149569 | biostudies-literature
Project description:Viruses target host proteins for degradation to enhance their replication and transmission, and identifying these targets has provided key insights into the host-pathogen interaction1-3. Here, we use complementary unbiased mass spectrometry-based approaches to dissect the widespread proteomeic remodelling seen in HIV-1 infected T-cells. Remarkably, the HIV accessory protein Vpr is both necessary and sufficient to cause the vast majority of these changes. Protein regulation requires recruitment of the DCAF1/DDB1/CUL4 E3 ubiquitin ligase complex, and pulsed-Stable Isotope Labelling with Amino Acids in Cell Culture (SILAC) and immunoprecipitation-mass spectrometry (IP-MS) identified at least 38 cellular proteins directly targeted for degradation by Vpr. Whilst other HIV-1 accessory proteins downregulate a small number of specific host factors, Vpr depletes multiple protein targets, causing systems-level changes to the cellular proteome. A subset of the novel cellular targets identified in this study are depleted by Vpr variants from across HIV-1/SIVcpz and other primate lentiviral lineages, confirming their biological importance in vivo.
2019-05-01 | PXD013221 | Pride
Project description:Viral infections, such as HIV, have been linked to obesity, but mechanistic evidence that they cause adipose dysfunction in vivo is lacking. We investigated a pathogenic role for the HIV-1 accessory protein viral protein R (Vpr), which can coactivate the glucocorticoid receptor (GR) and co-repress peroxisome proliferator-activated receptor ? (PPAR?) in vitro, in HIV-associated adipose dysfunction. Vpr circulated in the blood of most HIV-infected patients tested, including those on antiretroviral therapy (ART) with undetectable viral load. Vpr-mediated mechanisms were dissected in vivo using mouse models expressing the Vpr transgene in adipose tissues and liver (Vpr-Tg) or infused with synthetic Vpr. Both models demonstrated accelerated whole-body lipolysis, hyperglycemia and hypertriglyceridemia, and tissue-specific findings. Fat depots in these mice had diminished mass, macrophage infiltration, and blunted PPAR? target gene expression but increased GR target gene expression. In liver, we observed blunted PPAR? target gene expression, steatosis with decreased adenosine monophosphate-activated protein kinase activity, and insulin resistance. Similar to human HIV-infected patients, Vpr circulated in the serum of Vpr-Tg mice. Vpr blocked differentiation in preadipocytes through cell cycle arrest, whereas in mature adipocytes, it increased lipolysis with reciprocally altered association of PPAR? and GR with their target promoters. These results delineate a distinct pathogenic sequence: Vpr, released from HIV-1 in tissue reservoirs after ART, can disrupt PPAR/GR co-regulation and cell cycle control to produce adipose dysfunction and hepatosteatosis. Confirmation of these mechanisms in HIV patients could lead to targeted treatment of the metabolic complications with Vpr inhibitors, GR antagonists, or PPAR?/PPAR? agonists.
| S-EPMC4009012 | biostudies-literature
Project description:HIV-1 modulates key host cellular pathways for successful replication and pathogenesis through viral proteins. By evaluating the hijacking of the host ubiquitination pathway by HIV-1 at the whole-cell level, we now show major perturbations in the ubiquitinated pool of the host proteins post-HIV-1 infection. Our overexpression- and infection-based studies of T cells with wild-type and mutant HIV-1 proviral constructs showed that Vpr is necessary and sufficient for reducing whole-cell ubiquitination. Mutagenic analysis revealed that the three leucine-rich helical regions of Vpr are critical for this novel function of Vpr, which was independent of its other known cellular functions. We also validated that this effect of Vpr was conserved among different subtypes (subtypes B and C) and circulating recombinants from Northern India. Finally, we establish that this phenomenon is involved in HIV-1-mediated diversion of host ubiquitination machinery specifically toward the degradation of various restriction factors during viral pathogenesis.HIV-1 is known to rely heavily on modulation of the host ubiquitin pathway, particularly for counteraction of antiretroviral restriction factors, i.e., APOBEC3G, UNG2, and BST-2, etc.; viral assembly; and release. Reports to date have focused on the molecular hijacking of the ubiquitin machinery by HIV-1 at the level of E3 ligases. Interaction of a viral protein with an E3 ligase alters its specificity to bring about selective protein ubiquitination. However, in the case of infection, multiple viral proteins can interact with this multienzyme pathway at various levels, making it much more complicated. Here, we have addressed the manipulation of ubiquitination at the whole-cell level post-HIV-1 infection. Our results show that HIV-1 Vpr is necessary and sufficient to bring about the redirection of the host ubiquitin pathway toward HIV-1-specific outcomes. We also show that the three leucine-rich helical regions of Vpr are critical for this effect and that this ability of Vpr is conserved across circulating recombinants. Our work, the first of its kind, provides novel insight into the regulation of the ubiquitin system at the whole-cell level by HIV-1.
| S-EPMC4136268 | biostudies-literature