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Correlation of Naturally Occurring HIV-1 Resistance to DEB025 with Capsid Amino Acid Polymorphisms
Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla 92037, California, USA
Southern Research Institute, Frederick, Maryland 21701, USA
Debiopharm SA, Forum “après-demain”, Chemin Messidor 5-7, Case postale 5911, CH-1002 Lausanne, Switzerland
Klinisches Institut fuer Virologie, Medizinische Universitaet Wien, 1095 Vienna, Austria
* Author to whom correspondence should be addressed.
Received: 1 March 2013; in revised form: 18 March 2013 / Accepted: 20 March 2013 / Published: 22 March 2013
Abstract: 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.
Keywords: DEB025; alisporivir; cyclophilin inhibitors; cyclosporines; HIV/retroviruses; HIV capsid; natural resistance
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Gallay, P.A.; Ptak, R.G.; Bobardt, M.D.; Dumont, J.-M.; Vuagniaux, G.; Rosenwirth, B. Correlation of Naturally Occurring HIV-1 Resistance to DEB025 with Capsid Amino Acid Polymorphisms. Viruses 2013, 5, 981-997.
Gallay PA, Ptak RG, Bobardt MD, Dumont J-M, Vuagniaux G, Rosenwirth B. Correlation of Naturally Occurring HIV-1 Resistance to DEB025 with Capsid Amino Acid Polymorphisms. Viruses. 2013; 5(3):981-997.
Gallay, Philippe A.; Ptak, Roger G.; Bobardt, Michael D.; Dumont, Jean-Maurice; Vuagniaux, Grégoire; Rosenwirth, Brigitte. 2013. "Correlation of Naturally Occurring HIV-1 Resistance to DEB025 with Capsid Amino Acid Polymorphisms." Viruses 5, no. 3: 981-997.