Correlation of Naturally Occurring HIV-1 Resistance to DEB025 with Capsid Amino Acid Polymorphisms
DEB025 (alisporivir) is a synthetic cyclosporine with inhibitory activity against human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV). It binds to cyclophilin A (CypA) and blocks essential functions of CypA in the viral replication cycles of both viruses. DEB025 inhibits clinical...
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MDPI AG
2013-03-01
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| Series: | Viruses |
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| Online Access: | http://www.mdpi.com/1999-4915/5/3/981 |
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| author | Brigitte Rosenwirth Jean-Maurice Dumont Grégoire Vuagniaux Michael D. Bobardt Philippe A. Gallay Roger G. Ptak |
| author_facet | Brigitte Rosenwirth Jean-Maurice Dumont Grégoire Vuagniaux Michael D. Bobardt Philippe A. Gallay Roger G. Ptak |
| author_sort | Brigitte Rosenwirth |
| collection | DOAJ |
| description | DEB025 (alisporivir) is a synthetic cyclosporine with inhibitory activity against human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV). It binds to cyclophilin A (CypA) and blocks essential functions of CypA in the viral replication cycles of both viruses. DEB025 inhibits clinical HIV-1 isolates in vitro and decreases HIV-1 virus load in the majority of patients. HIV-1 isolates being naturally resistant to DEB025 have been detected in vitro and in nonresponder patients. By sequence analysis of their capsid protein (CA) region, two amino acid polymorphisms that correlated with DEB025 resistance were identified: H87Q and I91N, both located in the CypA-binding loop of the CA protein of HIV-1. The H87Q change was by far more abundant than I91N. Additional polymorphisms in the CypA-binding loop (positions 86, 91 and 96), as well as in the N-terminal loop of CA were detected in resistant isolates and are assumed to contribute to the degree of resistance. These amino acid changes may modulate the conformation of the CypA-binding loop of CA in such a way that binding and/or isomerase function of CypA are no longer necessary for virus replication. The resistant HIV-1 isolates thus are CypA-independent. |
| first_indexed | 2024-04-11T23:37:42Z |
| format | Article |
| id | doaj.art-2482db037e7b462e9f372e0cb101db58 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-04-11T23:37:42Z |
| publishDate | 2013-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-2482db037e7b462e9f372e0cb101db582022-12-22T03:56:53ZengMDPI AGViruses1999-49152013-03-015398199710.3390/v5030981Correlation of Naturally Occurring HIV-1 Resistance to DEB025 with Capsid Amino Acid PolymorphismsBrigitte RosenwirthJean-Maurice DumontGrégoire VuagniauxMichael D. BobardtPhilippe A. GallayRoger G. PtakDEB025 (alisporivir) is a synthetic cyclosporine with inhibitory activity against human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV). It binds to cyclophilin A (CypA) and blocks essential functions of CypA in the viral replication cycles of both viruses. DEB025 inhibits clinical HIV-1 isolates in vitro and decreases HIV-1 virus load in the majority of patients. HIV-1 isolates being naturally resistant to DEB025 have been detected in vitro and in nonresponder patients. By sequence analysis of their capsid protein (CA) region, two amino acid polymorphisms that correlated with DEB025 resistance were identified: H87Q and I91N, both located in the CypA-binding loop of the CA protein of HIV-1. The H87Q change was by far more abundant than I91N. Additional polymorphisms in the CypA-binding loop (positions 86, 91 and 96), as well as in the N-terminal loop of CA were detected in resistant isolates and are assumed to contribute to the degree of resistance. These amino acid changes may modulate the conformation of the CypA-binding loop of CA in such a way that binding and/or isomerase function of CypA are no longer necessary for virus replication. The resistant HIV-1 isolates thus are CypA-independent.http://www.mdpi.com/1999-4915/5/3/981DEB025alisporivircyclophilin inhibitorscyclosporinesHIV/retrovirusesHIV capsidnatural resistance |
| spellingShingle | Brigitte Rosenwirth Jean-Maurice Dumont Grégoire Vuagniaux Michael D. Bobardt Philippe A. Gallay Roger G. Ptak Correlation of Naturally Occurring HIV-1 Resistance to DEB025 with Capsid Amino Acid Polymorphisms Viruses DEB025 alisporivir cyclophilin inhibitors cyclosporines HIV/retroviruses HIV capsid natural resistance |
| title | Correlation of Naturally Occurring HIV-1 Resistance to DEB025 with Capsid Amino Acid Polymorphisms |
| title_full | Correlation of Naturally Occurring HIV-1 Resistance to DEB025 with Capsid Amino Acid Polymorphisms |
| title_fullStr | Correlation of Naturally Occurring HIV-1 Resistance to DEB025 with Capsid Amino Acid Polymorphisms |
| title_full_unstemmed | Correlation of Naturally Occurring HIV-1 Resistance to DEB025 with Capsid Amino Acid Polymorphisms |
| title_short | Correlation of Naturally Occurring HIV-1 Resistance to DEB025 with Capsid Amino Acid Polymorphisms |
| title_sort | correlation of naturally occurring hiv 1 resistance to deb025 with capsid amino acid polymorphisms |
| topic | DEB025 alisporivir cyclophilin inhibitors cyclosporines HIV/retroviruses HIV capsid natural resistance |
| url | http://www.mdpi.com/1999-4915/5/3/981 |
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