Special Issue "Cyclophilins and Viruses"

Guest Editor
Prof. Dr. Hengli Tang
Associate Professor, Department of Biological Science, Florida State University, 319 Stadium Dr., Tallahassee, FL 32304, USA
Website: http://www.bio.fsu.edu/faculty-tang.php
E-Mail: tang@bio.fsu.edu
Phone: +850 645 2403
Fax: +850 645 8447
Interests: virus-host cell interactions; antiviral drugs and resistance; cellular cofactors for viral infection; hepatitis C virus; HIV; stem cells and differentiation; cell culture models for viral infection

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• hepatitis C virus
• HIV/retroviruses
• coronavirus
• human cytomegalovirus
• influenza virus
• TRIM5-Cyp Fusion
• cyclophilin Inhibitors
• cyclosporine A
• alisporivir
• HIV capsid
• viral replication
• drug target
• cellular cofactor chaperone
• peptidyl-prolyl isomerase

Type of Paper: Review
Title: Emerging Role of Cyclophilins in the Life Cycles of Diverse Viruses
Authors: Stephen Frausto, Emily Lee, and Hengli Tang*
Affiliation: Department of Biology, The Florida State University, Tallahassee, Florida 32306, USA. *Author to whom correspondence should be addressed: E‐mail: tang@bio.fsu.edu; Tel.: +1‐850‐645‐2402; Fax: +1‐850‐645‐8447.
Abstract: Cyclophilins are peptidyl‐prolyl cis/trans isomerases that play important functions in protein folding. Mounting evidence supports varied roles of cyclophilins, in particular the ubiquitous Cyclophilin A (CyPA), in the support and/or repression of diverse viral life cycles. A picture of cyclophilins as broad regulators of viral‐host interactions is emerging, but the nature and mechanisms of these roles are not well defined. Interest in the cyclophilins is buoyed in particular by the clinical trial success of nonimmunomodulatory cyclophilin inhibitors (CPIs), including Alisporivir, in the treatment of hepatitis C virus. In addition, as cyclophilins are implicated in the predisposition to, or severity of, various diseases, the ability to more specifically and effectively modulate their function will prove increasingly useful. This review briefly summarizes the evidence of cyclophilins as key mediators of viral infection and their potential as drug targets.
Keywords: Cyclophilin, Immunophilin, Cyclosporins A, Host‐virus interactions

Type of Paper: Review
Title: Suppression of Coronavirus Replication by Cyclophilin Inhibitor
Authors: Yoshikazu Tanaka ^1,*, Yuka Sato ² and Takashi Sasaki ³
Affiliation: ¹ Department of Veterinary Hygiene, Veterinary School, Nippon Veterinary & Life Science University, Tokyo, Japan, ²The Institute of Medical Science, Division of Molecular Virology, Department of Microbiology and Immunology, The University of Tokyo, Tokyo, Japan, ³Laboratory of Bacterial Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, Tokyo, Japan.  *Corresponding author. Address correspondence to: Department of Veterinary Hygiene, Veterinary School, Nippon Veterinary & Life Science University, 1-7-1 Kyounan, Musashino, Tokyo 180-8602, Japan.  E-mail: ytanaka@nvlu.ac.jp, Tel: * 81-422-31-4151, Fax: *81-422-30-7502.
Abstract: Coronaviruses that infect a variety of mammalian and avian species cause serious diseases in human, cats, mice, and birds as the severe acute respiratory syndrome (SARS), feline infectious peritonitis (FIP), mouse hepatitis, and avian infectious bronchitis (IBR).  Neither effective vaccines nor treatment have been developed for SARS-coronavirus. It has been reported that a cyclophilin inhibitor, cyclosporin A (CsA) could inhibit the replication of coronaviruses. CsA has been well known as an immunosuppressive drug that binds cellular cyclophilins to inhibit calcineurin, a calcium-calmodulin-activated serine/threonine specific phosphatase.  The inhibition of calcineurin blocks the translocation of nuclear factor of activated T cells (NF-AT) from the cytosol to the nucleus, thus preventing the transcription of genes encoding cytokines such as interleukin-2.  Cyclophilins are peptidyl-prolyl isomerase (PPIase) and the physiological function of cyclophilin PPIase activity has been for many years described as a chaperone or foldase.  Also, many viruses require cyclophilins for their replication; these include human immunodeficiency virus (HIV-1), vesicular stomatitis virus (VSV), hepatitis C virus (HCV).  However, the molecular mechanisms of suppression on viral replication are distinct for different viruses. This review describes the suppressive effects of CsA on coronavirus replication.

Type of Paper: Article
Title: Correlation of Naturally Occurring HIV-1 Resistance to DEB025 with Capsid Amino Acid Polymorphisms
Authors: Philippe A. Gallay1, Roger G. Ptak2, Michael D. Bobardt1, Jean-Maurice Dumont3*, Grégoire Vuagniaux3 and Brigitte Rosenwirth4
Affiliations: 1 Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla 92037, California, USA; 2 Southern Research Institute, Frederick, Maryland 21701, USA; 3 Debiopharm, 1002 Lausanne, Switzerland; 4 Klinisches Institut fuer Virologie, Medizinische Universitaet Wien, 1095 Vienna, Austria; *    Author to whom correspondence should be addressed: e-mail: jmdumont@debiopharm.com; Mailing address: Debiopharm SA, Forum “après-demain”, Chemin Messidor 5-7, Case postale 5911, CH-1002 Lausanne, Switzerland; Phone: +41 21 3210111; Fax: +41 21 3210169.
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 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