Host cyclophilin A mediates HIV-1 attachment to target cells via heparans

Saphire, Andrew C. S.

doi:10.1093/emboj/18.23.6771

Cited by 165 publications

(162 citation statements)

References 43 publications

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“…Our findings that HSPGs promote initial HIV-1 attachment to and entry into BMECs are in accordance with previous studies including ours, which showed that HSPGs (i.e., syndecans) greatly enhance HIV-1 adsorption onto cells that express CD4 such as macrophages (76), CD4 ϩ HeLa cells (53,75), CD4 ϩ -T-cell lines (38,62,63,73,97), or cells that lack CD4, such as primary human vein endothelial cells (15), human genital epithelial cells (94), or HeLa cells (53). This finding is also consistent with a recent study, which showed that the uptake of the basic fibroblast growth factor by the BBB is greatly enhanced by cell surface HSPGs (21).…”

Section: Discussionsupporting

confidence: 93%

“…Several receptors have been reported to facilitate HIV-1 entry into CD4-negative cells. Specifically, galactosyl ceramide (34,35,95), adhesion molecules such as ICAM-1 and LFA-1 (27,28,72), C-type lectins such as DC-SIGN, DC-SIGNR, langerin, and the mannose receptor (12,30,66,87), and proteoglycans containing chondroitin or heparan sulfate proteoglycan chains (CSPGs or HSPGs, respectively) (8,15,53,75,94) have all been shown to promote HIV-1 attachment and/or entry into cells that lack CD4. To date, there is no demonstration that these receptors are capable of mediating fusion between viral and cellular membranes.…”

mentioning

confidence: 99%

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Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

Bobardt

Salmon

Wang

et al. 2004

J Virol

105

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As a neurotropic virus, human immunodeficiency virus type 1 (HIV-1) invades the brain and causes severe neuronal, astrocyte, and myelin damage in AIDS patients. To gain access to the brain, HIV-1 must migrate through brain microvascular endothelial cells (BMECs), which compose the blood-brain barrier (BBB). Given that BMECs lack the entry receptor CD4, HIV-1 must use receptors distinct from CD4 to enter these cells. We previously reported that cell surface proteoglycans serve as major HIV-1 receptors on primary human endothelial cells. In this study, we examined whether proteoglycans also impact cell-free HIV-1 invasion of the brain. Using an artificial BBB transmigration assay, we found that both heparan and chondroitin sulfate proteoglycans (HSPGs and CSPGs, respectively) are abundantly expressed on primary BMECs and promote HIV-1 attachment and entry. In contrast, the classical entry receptors, CXCR4 and CCR5, only moderately enhanced these processes. HSPGs and CSPGs captured HIV-1 in a gp120-dependent manner. However, no correlation between coreceptor usage and transmigration was identified. Furthermore, brain-derived viruses did not transmigrate more efficiently than lymphoid-derived viruses, suggesting that the ability of HIV-1 to replicate in the brain does not correlate with its capacity to migrate through the BBB as cell-free virus. Given that HIV-1-proteoglycan interactions are based on electrostatic contacts between basic residues in gp120 and sulfate groups in proteoglycans, HIV-1 may exploit these interactions to rapidly enter and migrate through the BBB to invade the brain.

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

Bobardt

Salmon

Wang

et al. 2004

J Virol

105

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“…However, we showed that heparinase I failed to remove HS on DCs, in contrast to heparinase II and III. This enzymatic specificity is not proteoglycan-dependent because heparinase I digests HS on macrophages (22), HeLa cells (23,31), and syndecan-expressing Namalwa cells (21), suggesting that HS composition on DCs differs from that on other cells. Heparinase I cleaves HS at the level of some highly O-sulfated disaccharides, heparinase III cleaves only at hexosaminic linkages with glucuronic acid in nonsulfated or Nsulfated disaccharides, and heparinase II cleaves a variety of HS forms (32).…”

Section: Discussionmentioning

confidence: 99%

Syndecan-3 is a dendritic cell-specific attachment receptor for HIV-1

Witte

Bobardt

Chatterji

et al. 2007

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

139

116

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“…Supernatants (70 l) were collected and protein concentration of cell lysates measured with a Coomassie-based Bio-Rad kit. The cell lysates were then subjected to Western blotting with antibodies to CypA (26), CypB (Zymed Laboratories Inc.), CypC (Protein Tech Group, Inc.), CypD (Calbiochem), NS5A (ViroStat), and NS5B (Alexis Biochemicals). Amido Black staining of the membranes confirmed that the loading of samples had been properly normalized.…”

Section: Methodsmentioning

confidence: 99%

The Isomerase Active Site of Cyclophilin A Is Critical for Hepatitis C Virus Replication

Chatterji

Bobardt

Selvarajah

et al. 2009

Journal of Biological Chemistry

178

220

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Cyclosporine A and nonimmunosuppressive cyclophilin (Cyp) inhibitors such as Debio 025, NIM811, and SCY-635 block hepatitis C virus (HCV) replication in vitro. This effect was recently confirmed in HCV-infected patients where Debio 025 treatment dramatically decreased HCV viral load, suggesting that Cyps inhibitors represent a novel class of anti-HCV agents. However, it remains unclear how these compounds control HCV replication. Recent studies suggest that Cyps are important for HCV replication. However, a profound disagreement currently exists as to the respective roles of Cyp members in HCV replication. In this study, we analyzed the respective contribution of Cyp members to HCV replication by specifically knocking down their expression by both transient and stable small RNA interference. Only the CypA knockdown drastically decreased HCV replication. The re-expression of an exogenous CypA escape protein, which contains escape mutations at the small RNA interference recognition site, restored HCV replication, demonstrating the specificity for the CypA requirement. We then mutated residues that reside in the hydrophobic pocket of CypA where proline-containing peptide substrates and cyclosporine A bind and that are vital for the enzymatic or the hydrophobic pocket binding activity of CypA. Remarkably, these CypA mutants fail to restore HCV replication, suggesting for the first time that HCV exploits either the isomerase or the chaperone activity of CypA to replicate in hepatocytes and that CypA is the principal mediator of the Cyp inhibitor anti-HCV activity. Moreover, we demonstrated that the HCV NS5B polymerase associates with CypA via its enzymatic pocket. The study of the roles of Cyps in HCV replication should lead to the identification of new targets for the development of alternate anti-HCV therapies. Hepatitis C virus (HCV)2 is the main contributing agent of acute and chronic liver diseases worldwide (1). Primary infection is often asymptomatic or associated with mild symptoms. However, persistently infected individuals develop high risks for chronic liver diseases such as hepatocellular carcinoma and liver cirrhosis (1). The combination of IFN␣ and ribavirin that serves as current therapy for chronically HCV-infected patients not only has a low success rate (about 50%) (2) but is often associated with serious side effects (2). There is thus an urgent need for the development of novel anti-HCV treatments (2).The immunosuppressive drug cyclosporine A (CsA) was reported to be clinically effective against HCV (3). Controlled trials showed that a combination of CsA with IFN␣ is more effective than IFN␣ alone, especially in patients with a high viral load (4, 5). Moreover, recent in vitro studies provided evidence that CsA prevents both HCV RNA replication and HCV protein production in an IFN␣-independent manner (6 -10). CsA exerts this anti-HCV activity independently of its immunosuppressive activity because the nonimmunosuppressive Cyp inhibitors such as Debio 025, NIM811, and SCY-635 also block HCV RNA and...

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Host cyclophilin A mediates HIV-1 attachment to target cells via heparans

Cited by 165 publications

References 43 publications

Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

Contribution of Proteoglycans to Human Immunodeficiency Virus Type 1 Brain Invasion

Syndecan-3 is a dendritic cell-specific attachment receptor for HIV-1

The Isomerase Active Site of Cyclophilin A Is Critical for Hepatitis C Virus Replication

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