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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Curr HIV Res 2010 Apr
PMID:The Vpu protein: new concepts in virus release and CD4 down-modulation. 2020 92

Investigation of the Vpu protein of HIV-1 recently uncovered a novel aspect of the mammalian innate response to enveloped viruses: retention of progeny virions on the surface of infected cells by the interferon-induced, transmembrane and GPI-anchored protein BST-2 (CD317; tetherin). BST-2 inhibits diverse families of enveloped viruses, but how it restricts viral release is unclear. Here, immuno-electron microscopic data indicate that BST-2 is positioned to directly retain nascent HIV virions on the plasma membrane of infected cells and is incorporated into virions. Virion-incorporation was confirmed by capture of infectivity using antibody to the ectodomain of BST-2. Consistent with a direct tethering mechanism, we confirmed that proteolysis releases restricted virions and further show that this removed the ectodomain of BST-2 from the cell surface. Unexpectedly, enzymatic cleavage of GPI anchors did not release restricted virions, weighing against models in which individual BST-2 molecules span the virion and host cell membranes. Although the exact molecular topology of restriction remains unsolved, we suggest that the incorporation of BST-2 into viral envelopes underlies its broad restrictive activity, whereas its relative exclusion from virions and sites of viral assembly by proteins such as HIV-1 Vpu may provide viral antagonism of restriction.
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PMID:Direct restriction of virus release and incorporation of the interferon-induced protein BST-2 into HIV-1 particles. 2022 43

HIV, a causative agent of AIDS, preferentially infects CD4+ T helper lymphocytes and leads to elimination of the host immune cells. Although the mechanisms that underlie the destruction of the immune system are not well understood, depletion of helper T lymphocytes, a hallmark of AIDS, is one of the pathogenesis of HIV. However, it has become apparent that host cells intrinsically harbor defense strategies against HIV infection. Existence of the intracellular restriction mechanisms can be expected to facilitate the design of new AIDS therapy. This review summarizes the HIV pathogenesis and the molecular aspects of recently identified intrinsic cellular restriction factors, APOBEC3G, TRIM5alpha, and Tetherin/BST-2.
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PMID:[HIV pathogenesis and intrinsic cellular defense mechanisms]. 2022 83

Advances in cell biology and biophysics revealed that cellular membranes consist of multiple microdomains with specific sets of components such as lipid rafts and TEMs (tetraspanin-enriched microdomains). An increasing number of enveloped viruses have been shown to utilize these microdomains during their assembly. Among them, association of HIV-1 (HIV type 1) and other retroviruses with lipid rafts and TEMs within the PM (plasma membrane) is well documented. In this review, I describe our current knowledge on interrelationships between PM microdomain organization and the HIV-1 particle assembly process. Microdomain association during virus particle assembly may also modulate subsequent virus spread. Potential roles played by microdomains will be discussed with regard to two post-assembly events, i.e., inhibition of virus release by a raft-associated protein BST-2/tetherin and cell-to-cell HIV-1 transmission at virological synapses.
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PMID:Relationships between plasma membrane microdomains and HIV-1 assembly. 2035 18

The Vpu accessory protein promotes HIV-1 release by counteracting Tetherin/BST-2, an interferon-regulated restriction factor, which retains virions at the cell-surface. Recent reports proposed beta-TrCP-dependent proteasomal and/or endo-lysosomal degradation of Tetherin as potential mechanisms by which Vpu could down-regulate Tetherin cell-surface expression and antagonize this restriction. In all of these studies, Tetherin degradation did not, however, entirely account for Vpu anti-Tetherin activity. Here, we show that Vpu can promote HIV-1 release without detectably affecting Tetherin steady-state levels or turnover, suggesting that Tetherin degradation may not be necessary and/or sufficient for Vpu anti-Tetherin activity. Even though Vpu did not enhance Tetherin internalization from the plasma membrane (PM), it did significantly slow-down the overall transport of the protein towards the cell-surface. Accordingly, Vpu expression caused a specific removal of cell-surface Tetherin and a re-localization of the residual pool of Tetherin in a perinuclear compartment that co-stained with the TGN marker TGN46 and Vpu itself. This re-localization of Tetherin was also observed with a Vpu mutant unable to recruit beta-TrCP, suggesting that this activity is taking place independently from beta-TrCP-mediated trafficking and/or degradation processes. We also show that Vpu co-immunoprecipitates with Tetherin and that this interaction involves the transmembrane domains of the two proteins. Importantly, this association was found to be critical for reducing cell-surface Tetherin expression, re-localizing the restriction factor in the TGN and promoting HIV-1 release. Overall, our results suggest that association of Vpu to Tetherin affects the outward trafficking and/or recycling of the restriction factor from the TGN and as a result promotes its sequestration away from the PM where productive HIV-1 assembly takes place. This mechanism of antagonism that results in TGN trapping is likely to be augmented by beta-TrCP-dependent degradation, underlining the need for complementary and perhaps synergistic strategies to effectively counteract the powerful restrictive effects of human Tetherin.
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PMID:Antagonism of tetherin restriction of HIV-1 release by Vpu involves binding and sequestration of the restriction factor in a perinuclear compartment. 2038 18

The restriction factor BST-2/tetherin contains two membrane anchors employed to retain some enveloped viruses, including HIV-1 tethered to the plasma membrane in the absence of virus-encoded antagonists. The 2.77 A crystal structure of the BST-2/tetherin extracellular core presented here reveals a parallel 90 A long disulfide-linked coiled-coil domain, while the complete extracellular domain forms an extended 170 A long rod-like structure based on small-angle X-ray scattering data. Mutagenesis analyses indicate that both the coiled coil and the N-terminal region are required for retention of HIV-1, suggesting that the elongated structure can function as a molecular ruler to bridge long distances. The structure reveals substantial irregularities and instabilities throughout the coiled coil, which contribute to its low stability in the absence of disulfide bonds. We propose that the irregular coiled coil provides conformational flexibility, ensuring that BST-2/tetherin anchoring both in the plasma membrane and in the newly formed virus membrane is maintained during virus budding.
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PMID:Structural basis of HIV-1 tethering to membranes by the BST-2/tetherin ectodomain. 2041 94

BST-2/tetherin is an interferon-inducible protein that restricts the release of enveloped viruses from the surface of infected cells by physically linking viral and cellular membranes. It is present at both the cell surface and in a perinuclear region, and viral anti-tetherin factors including HIV-1 Vpu and HIV-2 Env have been shown to decrease the cell surface population. To map the domains of human tetherin necessary for both virus restriction and sensitivity to viral anti-tetherin factors, we constructed a series of tetherin derivatives and assayed their activity. We found that the cytoplasmic tail (CT) and transmembrane (TM) domains of tetherin alone produced its characteristic cellular distribution, while the ectodomain of the protein, which includes a glycosylphosphatidylinositol (GPI) anchor, was sufficient to restrict virus release when presented by the CT/TM regions of a different type II membrane protein. To counteract tetherin restriction and remove it from the cell surface, HIV-1 Vpu required the specific sequence present in the TM domain of human tetherin. In contrast, the HIV-2 Env required only the ectodomain of the protein and was sensitive to a point mutation in this region. Strikingly, the anti-tetherin factor, Ebola virus GP, was able to overcome restriction conferred by both tetherin and a series of functional tetherin derivatives, including a wholly artificial tetherin molecule. Moreover, GP overcame restriction without significantly removing tetherin from the cell surface. These findings suggest that Ebola virus GP uses a novel mechanism to circumvent tetherin restriction.
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PMID:Ebola virus glycoprotein counteracts BST-2/Tetherin restriction in a sequence-independent manner that does not require tetherin surface removal. 2044 95

The interferon-induced BST-2 protein has the unique ability to restrict the egress of HIV-1, Kaposi's sarcoma-associated herpesvirus (KSHV), Ebola virus, and other enveloped viruses. The observation that virions remain attached to the surface of BST-2-expressing cells led to the renaming of BST-2 as "tetherin". However, viral proteins such as HIV-1 Vpu, simian immunodeficiency virus Nef, and KSHV K5 counteract BST-2, thereby allowing mature virions to readily escape from infected cells. Since the anti-viral function of BST-2 was discovered, there has been an explosion of research into several aspects of this intriguing interplay between host and virus. This review focuses on recent work addressing the molecular mechanisms involved in BST-2 restriction of viral egress and the species-specific countermeasures employed by various viruses.
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PMID:The great escape: viral strategies to counter BST-2/tetherin. 2048 22

Basic science continues to occupy a substantial portion of the program at the Conference on Retroviruses and Opportunistic Infections. At the 17th conference this year, presentations focused on advances in our understanding of cellular factors that regulate the interplay between the virus and the host cell and, in particular, cellular defenses such as tetherin (or BST-2) that antagonize viral replication. Research into basic mechanisms of primate lentiviral pathogenicity was also an area of great interest at the conference. An analysis of the evolution of lentiviral and primate genomes highlights the conflict between the virus and its host and illustrates the considerable gyrations that lentiviruses have undergone to acquire the ability to replicate within their primate hosts. It is now apparent that all 4 accessory proteins of lentiviruses are in some way involved in overcoming natural antiviral restrictions in primate cells. Therefore, because lentiviruses such as HIV-1 are hard pressed to avoid the intrinsic antiviral defenses of the cell, there is strong rationale for the development of strategies that harness the antiviral capacity of these natural cellular restrictions.
Top HIV Med
PMID:Advances in basic science. 2051 21

The IFN-inducible antiviral protein tetherin (or BST-2/CD317/HM1.24) impairs release of mature HIV-1 particles from infected cells. HIV-1 Vpu antagonizes the effect of tetherin. The fate of virions trapped at the cell surface remains poorly understood. Here, we asked whether tetherin impairs HIV cell-to-cell transmission, a major means of viral spread. Tetherin-positive or -negative cells, infected with wild-type or DeltaVpu HIV, were used as donor cells and cocultivated with target lymphocytes. We show that tetherin inhibits productive cell-to-cell transmission of DeltaVpu to targets and impairs that of WT HIV. Tetherin accumulates with Gag at the contact zone between infected and target cells, but does not prevent the formation of virological synapses. In the presence of tetherin, viruses are then mostly transferred to targets as abnormally large patches. These viral aggregates do not efficiently promote infection after transfer, because they accumulate at the surface of target cells and are impaired in their fusion capacities. Tetherin, by imprinting virions in donor cells, is the first example of a surface restriction factor limiting viral cell-to-cell spread.
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PMID:Tetherin restricts productive HIV-1 cell-to-cell transmission. 2058 62


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