Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Vpu accessory gene that originated in the primate lentiviral lineage leading to human immunodeficiency virus type 1 is an antagonist of human tetherin/BST-2 restriction. Most other primate lentivirus lineages, including the lineage represented by simian immunodeficiency virus SIVagm from African green monkeys (AGMs), do not encode Vpu. While some primate lineages encode gene products other than Vpu that overcome tetherin/BST-2, we find that SIVagm does not antagonize physiologically relevant levels of AGM tetherin/BST-2. AGM tetherin/BST-2 can be induced by low levels of type I interferon and can potently restrict two independent strains of SIVagm. Although SIVagm Nef had an effect at low levels of AGM tetherin/BST-2, simian immunodeficiency virus SIVmus Vpu, from a virus that infects the related monkey Cercopithecus cephus, is able to antagonize even at high levels of AGM tetherin/BST-2 restriction. We propose that since the replication of SIVagm does not induce interferon production in vivo, tetherin/BST-2 is not induced, and therefore, SIVagm does not need Vpu. This suggests that primate lentiviruses evolve tetherin antagonists such as Vpu or Nef only if they encounter tetherin during the typical course of natural infection.
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PMID:Simian immunodeficiency virus SIVagm from African green monkeys does not antagonize endogenous levels of African green monkey tetherin/BST-2. 1972 8

Tetherin (CD317/BST-2), an interferon-induced membrane protein, restricts the release of nascent retroviral particles from infected cell surfaces. While human immunodeficiency virus type 1 (HIV-1) encodes the accessory gene vpu to overcome the action of tetherin, the lineage of primate lentiviruses that gave rise to HIV-2 does not. It has been previously reported that the HIV-2 envelope glycoprotein has a Vpu-like function in promoting virus release. Here we demonstrate that the HIV-2 Rod envelope glycoprotein (HIV-2 Rod Env) is a tetherin antagonist. Expression of HIV-2 Rod Env, but not that of HIV-1 or the closely related simian immunodeficiency virus (SIV) SIVmac1A11, counteracts tetherin-mediated restriction of Vpu-defective HIV-1 in a cell-type-specific manner. This correlates with the ability of the HIV-2 Rod Env to mediate cell surface downregulation of tetherin. Antagonism requires an endocytic motif conserved across HIV/SIV lineages in the gp41 cytoplasmic tail, but specificity for tetherin is governed by extracellular determinants in the mature Env protein. Coimmunoprecipitation studies suggest an interaction between HIV-2 Rod Env and tetherin, but unlike studies with Vpu, we found no evidence of tetherin degradation. In the presence of HIV-2 Rod Env, tetherin localization is restricted to the trans-Golgi network, suggesting Env-mediated effects on tetherin trafficking sequester it from virus assembly sites on the plasma membrane. Finally, we recapitulated these observations in HIV-2-infected CD4+ T-cell lines, demonstrating that tetherin antagonism and sequestration occur at physiological levels of Env expression during virus replication.
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PMID:Antagonism to and intracellular sequestration of human tetherin by the human immunodeficiency virus type 2 envelope glycoprotein. 1974 Sep 80

The human immunodeficiency virus type 1 (HIV-1) accessory protein Vpu enhances virus particle release by counteracting a host factor that retains virions at the surfaces of infected cells. It was recently demonstrated that cellular protein BST-2/CD317/Tetherin restricts HIV-1 release in a Vpu-dependent manner. Calcium-modulating cyclophilin ligand (CAML) was also proposed to be involved in this process. We investigated whether CAML is involved in cell surface expression of Tetherin. Here, we show that CAML overexpression in permissive Cos-7 cells or CAML depletion in restrictive HeLa cells has no effect on HIV-1 release or on Tetherin surface expression, indicating that CAML is not required for Tetherin-mediated restriction of HIV-1 release.
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PMID:Effect of calcium-modulating cyclophilin ligand on human immunodeficiency virus type 1 particle release and cell surface expression of tetherin. 1979 20

Bone marrow stromal antigen 2 (BST-2, also known as tetherin) is a recently identified interferon-inducible host restriction factor that can block the production of enveloped viruses by trapping virus particles at the cell surface. This antiviral effect is counteracted by the human immunodeficiency virus type 1 (HIV-1) accessory protein viral protein U (Vpu). Here we show that HIV-1 Vpu physically interacts with BST-2 through their mutual transmembrane domains and leads to the degradation of this host factor via a lysosomal, not proteasomal, pathway. The degradation is partially controlled by a cellular protein, beta-transducin repeat-containing protein (betaTrCP), which is known to be required for the Vpu-induced degradation of CD4. Importantly, targeting of BST-2 by Vpu occurs at the plasma membrane followed by the active internalization of this host protein by Vpu independently of constitutive endocytosis. Thus, the primary site of action of Vpu is the plasma membrane, where Vpu targets and internalizes cell-surface BST-2 through transmembrane interactions, leading to lysosomal degradation, partially in a betaTrCP-dependent manner. Also, we propose the following configuration of BST-2 in tethering virions to the cell surface; each of the dimerized BST-2 molecules acts as a bridge between viral and cell membranes.
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PMID:HIV-1 accessory protein Vpu internalizes cell-surface BST-2/tetherin through transmembrane interactions leading to lysosomes. 1983 71

Tetherin is an IFN-inducible restriction factor that inhibits HIV-1 particle release in the absence of the HIV-1 countermeasure, viral protein U (Vpu). Although ubiquitous in HIV-1 and simian immunodeficiency viruses from chimpanzees, greater spot nosed monkeys, mustached monkeys, and Mona monkeys, other primate lentiviruses do not encode a Vpu protein. Here we demonstrate that SIV from Tantalus monkeys (SIVtan) encodes an envelope glycoprotein (SIVtan Env) able to counteract tetherin from Tantalus monkeys, rhesus monkeys, sooty mangabeys, and humans, but not from pigs. We show that sensitivity to Vpu but not SIVtan Env can be transferred with the human tetherin transmembrane region. We also identify a mutation in the tetherin extracellular domain, which almost completely abolishes sensitivity of human tetherin to SIVtan Env without compromising antiviral activity or sensitivity to Vpu. SIVtan Env expression results in a reduction of surface tetherin, as well as reduction in tetherin co-localization with mature surface-associated virus. Immuno-electron microscopy reveals co-localization of SIVtan Env with tetherin in intracellular tubulo-vesicular structures, suggesting that tetherin is sequestered away from budding virions at the cell surface. Along with HIV-1 Vpu and SIV Nef, envelope glycoprotein is the third and most broadly active lentiviral-encoded tetherin countermeasure to be described. Our observations emphasize the importance of tetherin in protecting mammals against viral infection and suggest that HIV-1 Vpu inhibitors may select active envelope mutants.
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PMID:Simian immunodeficiency virus envelope glycoprotein counteracts tetherin/BST-2/CD317 by intracellular sequestration. 1986 25

CD317/Bst-2/tetherin is a host factor that restricts the release of human immunodeficiency virus type 1 (HIV-1) by trapping virions at the plasma membrane of certain producer cells. It is antagonized by the HIV-1 accessory protein Vpu. Previous light microscopy studies localized CD317 to the plasma membrane and the endosomal compartment and showed Vpu induced downregulation. In the present study, we performed quantitative immunoelectron microscopy of CD317 in cells producing wild-type or Vpu-defective HIV-1 and in control cells. Double-labeling experiments revealed that CD317 localizes to the plasma membrane, to early and recycling endosomes, and to the trans-Golgi network. CD317 largely relocated to endosomes upon HIV-1 infection, and this effect was partly counteracted by Vpu. Unexpectedly, CD317 was enriched in the membrane of viral buds and cell-associated and cell-free viruses compared to the respective plasma membrane, and this enrichment was independent of Vpu. These results suggest that the tethering activity of CD317 critically depends on its density at the cell surface and appears to be less affected by its density in the virion membrane.
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PMID:CD317/tetherin is enriched in the HIV-1 envelope and downregulated from the plasma membrane upon virus infection. 2014 89

Vpu antagonizes human immunodeficiency virus type 1 (HIV-1) particle release inhibition by CD317/BST-2/Tetherin. Whether this Vpu activity strictly requires cellular depletion of the restriction factor is unclear. Here, we characterized CD317 variants with mutations in putative sorting or ubiquitination motifs. All mutants still potently impaired release of Vpu-defective HIV-1 and remained sensitive to Vpu-mediated release enhancement. Importantly, this virological antagonism correlated with surface downregulation of CD317 mutants by Vpu, while intracellular pools of these mutants, which were consistently depleted of the wild-type protein, were highly variable or even enhanced. Thus, Vpu can efficiently antagonize virion tethering in the absence of CD317 degradation.
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PMID:Antagonism of CD317 restriction of human immunodeficiency virus type 1 (HIV-1) particle release and depletion of CD317 are separable activities of HIV-1 Vpu. 2014 95

Plasmacytoid dendritic cells (pDCs) are bone marrow-derived cells that secrete large amounts of type I interferon (IFN) in response to viruses. Type I IFNs are pleiotropic cytokines with antiviral activity that also enhance innate and adaptive immune responses. Viruses trigger activation of pDCs and type I IFN responses mainly through the Toll-like receptor pathway. However, a variety of activating and inhibitory pDC receptors fine tune the amplitude of type I IFN responses. Chronic activation and secretion of type I IFN in the absence of infection can promote autoimmune diseases. Furthermore, while activated pDCs promote immunity and autoimmunity, resting or alternatively activated pDCs may be tolerogenic. The various roles of pDCs have been extensively studied in vitro and in vivo with depleting antibodies. However, depleting antibodies cross-react with other cell types that are critical for eliciting protective immunity, potentially yielding ambiguous phenotypes. Here we discuss new approaches to assess pDC functions in vivo and provide preliminary data on their potential roles during viral infections. Such approaches would also prove useful in the more specific evaluation of how pDCs mediate tolerance and autoimmunity. Finally, we discuss the emergent role of pDCs and one of their receptors, tetherin, in human immunodeficiency virus pathogenesis.
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PMID:Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. 2019 17

Human immunodeficiency virus type 1 (HIV-1) and several simian immunodeficiency viruses (SIV) encode for a transmembrane protein known as Vpu (viral protein U). While one of the smallest of the HIV-1 proteins, it has two important functions within virus-infected cells. The first of these functions is the down-regulation of the CD4 receptor to prevent its interaction with the HIV-1 envelope glycoprotein. Vpu interacts with the CD4 receptor in the rough endoplasmic reticulum (RER), resulting in its re-translocation across the RER and subsequent degradation via the proteasomal pathway. The second major function of the Vpu protein is to facilitate release of virus from infected cells. Previous studies have shown that virus release is cell type specific, suggesting that certain cells may express a restriction factor that inhibits virus release in the absence of Vpu. Recently, bone marrow stromal antigen 2 (BST-2/HM1.24/CD317/tetherin) has been identified as this factor. This review will focus on new findings within the last four years on the role of Vpu in CD4 down-regulation and the restriction of virus release from cells. We will relate these findings to virus pathogenesis and propose questions regarding BST-2 as a restriction factor.
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PMID:The Vpu protein: new concepts in virus release and CD4 down-modulation. 2020 92

Toll-like receptor-3 (TLR-3) recognizes double-stranded RNA and induces multiple intracellular events responsible for innate anti-viral immunity against a number of viral infections. Activation of TLR-3 inhibits human immunodeficiency virus (HIV) replication, but the mechanism(s) underlying the action of TLR-3 activation on HIV are largely unknown. Here we demonstrate that treatment of monocyte-derived macrophages with poly I:C, a synthetic ligand for TLR-3, significantly inhibited HIV infection and replication. Investigation of the mechanisms showed that TLR-3 activation resulted in the induction of type I interferon inducible antiviral factors, including APOBEC3G and tetherin, the newly identified anti-HIV cellular proteins. In addition, poly I:C-treated macrophages expressed increased levels of CC chemokines, the ligands for CCR5. Furthermore, TLR-3 activation in macrophages induced the expression of cellular microRNAs (miRNA-28, -125b, -150, -223 and -382), the newly identified intracellular HIV restriction factors. These findings indicate that TLR-3-mediated induction of multiple anti-HIV factors should be beneficial for the treatment of HIV disease where innate immune responses are compromised by the virus.
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PMID:A critical function of toll-like receptor-3 in the induction of anti-human immunodeficiency virus activities in macrophages. 2063 39


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