Figure 1. Replication cycles of HCV, HBV and HIV and points of intervention by HDTs.
a I Upon entry of hepatitis C virus (HCV) into the cell, viral RNA is translated at the endoplasmic reticulum (ER) and a membranous replication factory is formed (a membranous web). There, viral RNA (vRNA) is amplified and packaged into nucleocapsids that bud into the ER. Enveloped virions are secreted out of the cell. b I In the case of HBV, upon virus entry, the partially double-stranded viral DNA genome is converted into the covalently closed circular DNA (cccDNA) form that persists as an episome in the nucleus. vRNAs are transcribed and used for protein synthesis. Within the nucleocapsids the vRNA pre-genome is reverse transcribed by the viral polymerase (red circle) and virions are formed by budding into the ER lumen. Virions are secreted from the cell, along with subviral particles (SVPs) that lack a nucleocapsid and so are non-infectious. SVPs are composed of the same envelope (Env) proteins as infectious HBV particles. c I HIV enters upon interaction with the CD4 receptor and a co-receptor (such as CCR5) by direct fusion of the viral envelope with the plasma membrane. Nucleocapsids that contain the RNA genome are released into the cytoplasm and upon reverse transcription a pre-integration complex (PIC) containing the viral integrase (green bar) is formed. The viral DNA genome (blue) is inserted into the host cell genome (light purple) and this provirus serves as a template for the transcription of all viral mRNAs (vRNAs). These are translated in the cytoplasm and give rise to HIV proteins; some of them (the Gag and Gag–Pol polyprotein precursors) are transported to the plasma membrane to trigger the formation of nucleocapsids. These nucleocapsids acquire their envelope by budding at the plasma membrane. The viral polyproteins are cleaved within the released virions, thus inducing a rearrangement of the structural proteins, visible by morphological conversion into a conical nucleocapsid. Only these particles are infectious. CypA, cyclophilin A; HBIGs, hepatitis B immunoglobulins; HDT, host-directed therapy; ISGs, interferon-stimulated genes; TCR, T cell receptor.