Identification of calcium-modulating cyclophilin ligand as a human host restriction to HIV-1 release overcome by Vpu

Varthakavi, Vasundhara; Heimann-Nichols, Ellen; Smith, Rita M.; Sun, Yuehui; Bram, Richard J.; Ali, Showkat; Rose, Jeremy J.; Ding, Ling; Spearman, Paul

doi:10.1038/nm1778

Cited by 37 publications

(40 citation statements)

References 32 publications

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“…Two possible explanations for this are (i) interaction of Vpu with a unknown host factor(s), which is required for the degradation of BST-2, and (ii) the existence of another host restriction factor antagonized by Vpu. Regarding the latter possibility, it is tempting to speculate that calcium-modulating cyclophilin ligand recently, identified as a Vpu-sensitive restriction factor (54), regulates the cell-surface expression of BST-2. Because calcium-modulating cyclophilin ligand plays a role in the recycling of the epidermal growth factor receptor through recycling endosomes (55) to which BST-2 is localized (49), calciummodulating cyclophilin ligand might be also required for the recycling of BST-2.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Accessory Protein Vpu Internalizes Cell-surface BST-2/Tetherin through Transmembrane Interactions Leading to Lysosomes

Iwabu

Fujita

Kinomoto

et al. 2009

Journal of Biological Chemistry

207

300

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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, ␤-transducin repeat-containing protein (␤TrCP), 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 ␤TrCP-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. Viral protein U (Vpu)2 is an 81-amino acid type I integral membrane phosphoprotein expressed by human immunodeficiency virus type 1 (HIV-1) (1, 2) and several simian immunodeficiency viruses (3-6). Vpu is not incorporated into virus particles (7), indicating that it acts exclusively in virus-producer cells. Indeed, Vpu is known to play two distinct roles during the later stages of infection. First, Vpu interacts with newly synthesized CD4 molecules complexed with the gp160 envelope glycoprotein precursor in the endoplasmic reticulum (8, 9) and recruits the ␤-transducin repeat-containing protein 1 (␤TrCP-1) subunit of the Skp1-Cullin1-F-box ubiquitin ligase complex (10) as well as ␤TrCP-2 (11) through its phosphoserine residues at positions 52 and 56 in the cytoplasmic (CT) domain (12,13). This event results in proteasome-mediated degradation of CD4 (10, 14, 15) allowing gp160 to resume transport toward the cell surface for virion incorporation. Second, Vpu mediates the enhancement of virion release (16 -18) in a cell type-dependent manner (e.g. HeLa cells require Vpu, whereas COS7 cells do not (19,20)), and its absence leads to the accumulation of viral particles at the cell surface (21).In contrast to the effect of Vpu on CD4 degradation, little had been known about the mechanism by which Vpu enhances the release of virions. The finding that HeLa-COS7 heterokaryons exhibited HeLa-type properties suggested that Vpu-responsive HeLa cells might harbor endogenous a restriction factor(s) that could be counteracted by this viral protein (22), as seen in Vifresponsive cells harboring the antiretroviral factor APOBEC3G counteracted by Vif (23). Neil et al. (24) showed that Vpu-deficient viral particles accumulated ...

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Section: Discussionmentioning

confidence: 99%

HIV-1 Accessory Protein Vpu Internalizes Cell-surface BST-2/Tetherin through Transmembrane Interactions Leading to Lysosomes

Iwabu

Fujita

Kinomoto

et al. 2009

Journal of Biological Chemistry

207

300

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“…It is possible that Bst-2 functions in concert with other host factor(s) (e.g., CAML). This would explain why silencing of either Bst-2 or CAML in HeLa cells resulted in Vpu-independent release of particles (24,29). It will therefore be interesting to investigate the potential functional interplay of Bst-2 and CAML.…”

Section: Discussionmentioning

confidence: 99%

“…Several host factors have since been implicated in the Vpu-sensitive inhibition of virus release, including Task-1 and UBP (20,21). More recently, two additional host factors, Bst-2/CD317/tetherin/HM1.24 (22,23) and calcium-modulating cyclophilin ligand (CAML) (24) have been correlated with Vpu-sensitive restriction of HIV-1 virus release.…”

Section: Hiv-1 Vpu Enhances the Release Of Virions From Infected Cellsmentioning

confidence: 99%

Vpu enhances HIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletion

Miyagi

Andrew

Kao

et al. 2009

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

205

281

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HIV-1 Vpu enhances the release of virions from infected cells. Recent work identified Bst-2/CD317/tetherin as a host factor whose inhibitory activity on viral release is counteracted by Vpu. A current working model proposes that Bst-2 inhibits virus release by tethering viral particles to the cell surface. Here, we analyzed endogenous Bst-2 with respect to its effect on virus release from HeLa cells, T cells, and macrophages. We noted significant cell type-dependent variation in Bst-2 expression. Vpu caused a reduction in Bst-2 expression in transfected HeLa cells and long-term infected macrophages. However, Vpu expression did not result in cell surface down-modulation of Bst-2 or a reduction in intracellular Bst-2 expression in CEMx174 or H9 cells, yet virus replication in these cells was Vpu-responsive. Surprisingly, Bst-2 was undetectable in cell-free virions that were recovered from the surface of HeLa cells by physical shearing, suggesting that a tethering model may not explain all of the functional properties of Bst-2. Taken together we conclude that enhancement of virus release by Vpu does not, at least in CEMx174 and H9 cells, require cell surface down-modulation or intracellular depletion of Bst-2, nor does it entail exclusion of Bst-2 from viral particles.

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“…Here, the impact of IFN on virus spread was slightly stronger for the ⌬Vpu virus than for the WT, but the defective virus finally managed to spread in the presence of the cytokine. This suggests that restriction factors counteracted by Vpu, like tetherin and calcium-modulating cyclophilin ligand (41,68), likely impair viral cell-to-cell transfer but do not totally block this mode of virus replication. Additionally, IFN treatment in cell cultures may only induce suboptimal or saturable levels of these antiviral proteins.…”

Section: Discussionmentioning

confidence: 99%

“…The viral protein Vpu promotes virion release from infected cells (56,65) by counteracting host restriction factors (40,68,69). At least one of these ϩ T lymphocytes were cultured in the presence of increasing concentrations of IFN-␣ (0 to 10,000 IU/ml) for 24 h and then exposed to HIV (1, 10, or 100 ng of p24/0.5 ml/10 6 cells).…”

Section: Inhibition Of Hiv Replication By Type I Ifn In Primary Tmentioning

confidence: 99%

Partial Inhibition of Human Immunodeficiency Virus Replication by Type I Interferons: Impact of Cell-to-Cell Viral Transfer

Vendrame

Sourisseau

Perrin

et al. 2009

J Virol

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Type I interferons (IFN) inhibit several steps of the human immunodeficiency virus type 1 (HIV) replication cycle. Some HIV proteins, like Vif and Vpu, directly counteract IFN-induced restriction factors. Other mechanisms are expected to modulate the extent of IFN inhibition. Here, we studied the impact of IFN on various aspects of HIV replication in primary T lymphocytes. We confirm the potent effect of IFN on Gag p24 production in supernatants. Interestingly, IFN had a more limited effect on HIV spread, measured as the appearance of Gag-expressing cells. Primary isolates displayed similar differences in the inhibition of p24 release and virus spread. Virus emergence was the consequence of suboptimal inhibition of HIV replication and was not due to the selection of resistant variants. Cell-to-cell HIV transfer, a potent means of virus replication, was less sensitive to IFN than infection by cell-free virions. These results suggest that IFN are less active in cell cultures than initially thought. They help explain the incomplete protection by naturally secreted IFN during HIV infection and the unsatisfactory outcome of IFN treatment in HIV-infected patients.The inhibition of human immunodeficiency virus type 1 (HIV) replication by type I interferons (IFN) was demonstrated soon after the discovery of the virus (4,16,20,23,49,71). Different steps of the virus cycle are sensitive to IFN (reviewed in references 24, 25, and 47). IFN treatment of primary T lymphocytes, macrophages, and some T-cell lines efficiently inhibits early phases of infection, including HIVinduced cell fusion and reverse transcription (15,16,26,27,46,60,61,70). IFN also impair later steps of the HIV replication cycle, ranging from reduced virus protein processing and stability to altered virion release and composition (2,8,17,19,20,23,26,28,39,49,63,71,72). In these early reports, the experimental systems were optimized to measure the effect of IFN on either early or late steps of the virus replication cycle but did not fully explore the long-term efficacy of IFN.Some potential IFN-induced anti-HIV effectors were identified. Both the protein kinase R and the 2Ј,5Ј-oligoadenylate synthetase-directed RNase L pathways are activated by HIV components and may participate in the inhibition of HIV replication (32, 37, 59). IFN-␣ treatment also enhances the expression of TRIM5␣ and APOBEC3G (6, 53), two cellular factors that mediate potent intrinsic immunity against HIV and other viruses (reviewed in references 33 and 66). Moreover, recent studies have characterized IFN-induced antiviral factors that decrease virus particle release. In particular, IFN-stimulated gene 15 (ISG15) interferes with the recruitment of the cellular machinery required for viral assembly (43), TRIM22 appears to perturb virus precursor protein trafficking (3), and BST-2/CD317/HM1.24 (also called tetherin) acts by tethering mature virus particles to the cell surface (41, 67).HIV counteracts some of these antiviral systems, confirming that endogenous IFN exert a selective pressure...

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Identification of calcium-modulating cyclophilin ligand as a human host restriction to HIV-1 release overcome by Vpu

Cited by 37 publications

References 32 publications

HIV-1 Accessory Protein Vpu Internalizes Cell-surface BST-2/Tetherin through Transmembrane Interactions Leading to Lysosomes

HIV-1 Accessory Protein Vpu Internalizes Cell-surface BST-2/Tetherin through Transmembrane Interactions Leading to Lysosomes

Vpu enhances HIV-1 virus release in the absence of Bst-2 cell surface down-modulation and intracellular depletion

Partial Inhibition of Human Immunodeficiency Virus Replication by Type I Interferons: Impact of Cell-to-Cell Viral Transfer

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