The role of immunophilins in viral infection

Abstract

Background: Tremendous progress has been made in the past 20 years in understanding the roles played by immunophilins, and in particular the cyclophilins, in supporting the replication cycles of human viruses. A growing body of genetic and biochemical evidence and data from clinical trials confirm that cyclophilins are essential cofactors that contribute to establishing a permissive environment within the host cell that supports the replication of HIV-1 and HCV. Cyclophilin A regulates HIV-1 replication kinetics and infectivity, modulates sensitivity to host restriction factors, and cooperates in the transit of the pre-integration complex into the nucleus of infected cells. Cyclophilin A is an essential cofactor whose expression supports HCV-specific RNA replication in human hepatocytes.

General significance: Peptidyl-prolyl isomerase inhibitors have been used in clinical trials to validate cyclophilins as antiviral targets for the treatment of HIV-1 and Chronic Hepatitis C virus infection and as molecular probes to identify the roles played by immunophilins in supporting the replication cycles of human viruses.

Scope of review: This review summarizes emerging research that defines the functions of immunophilins in supporting the replication cycles of HIV-1, HCV, HBV, coronaviruses, and other viral pathogens and describes new information that suggests a role for immunophilins in regulating innate immune responses against chronic viral infection.

Major conclusions: The dependence on cyclophilins by evolutionarily distinct viruses for accomplishing various steps in replication such as viral entry, initiation of genomic nucleic acid replication, viral genome uncoating, nuclear import and nuclear entry, emphasizes the potential of cyclophilin inhibitors as therapeutic agents. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets.

Keywords: Cyclophilin inhibitors; Cyclophilins; HCV; HIV-1; Immunophilins; Viruses.

Fig. 1

Models for the respective roles of cyclophilin A in HIV-1 (top model) and HCV infection (bottom model). HIV-1: Immediately after viral entry and delivery of the viral capsid core into the cytosol of the target cell, cyclophilin A binds to the capsid core that surrounds the viral genome and preserves the stability of the core during its transport to the nucleus. After docking to the nucleopore via specific components of the nucleopore complex such as Nup358/RANBP2 and Nup153, the viral genome undergoes the so-called core uncoating allowing the passage of the viral genome through the nucleopore and its integration into the host DNA. Cyclophilin inhibitors by binding to the enzymatic pocket of cyclophilin A prevent its binding to the incoming capsid core. In the absence of cyclophilin A, the capsid core is destabilized and brakes apart allowing the recognition of the viral genome by cellular sensors resulting in its degradation. HCV: After entry, the viral RNA is decapsidated and used both for polyprotein translation and replication in the cytoplasm. Translation occurs at rough endoplasmic reticulum (ER) and produces single polyprotein, which is then cleaved by cellular and viral proteases, to produce structural and nonstructural proteins (NS). Replication and post-translational processing take place in a membranous web made of NS and host proteins located at the perinuclear membrane. Cyclophilin A by binding to the membrane-anchored NS5A protein triggers the creation of double membrane vesicles (DMVs). In this new membranous compartment, HCV RNA occurs in a protected manner. In the presence of cyclophilin inhibitors, cyclophilin A is unable to bind to NS5A and to mediate DMVs. Unprotected viral RNA and proteins are now exposed to cellular sensors and degradation.