RNA structural switches and long-distance interactions regulate the balance between genome replication, packaging, and translation. (a) The HCV life cycle is regulated by a complex network of long-distance intra-molecular interactions and inter-molecular interactions. The packaging site which binds to the HCV core protein resides in the 3′ untranslated region (3′UTR). A long-distance base pairing between the cis-acting element (CRE) in the coding region and the X-tail in the 3′UTR regulates the balance between replication and packaging (light green dotted line). A long-distance interaction between the CRE and the internal ribosome entry site (IRES) regulates the balance between replication and translation (dark green dotted line). The 3′UTR is alternatively structured, leading to the formation of homodimers through an intermolecular interaction. The HCV 5′UTR binds the host microRNA miR-122 to regulate different aspects of HCV replication; (b) A structural switch in the HIV-1 5′UTR regulates the balance between genome translation and packaging. Transcripts beginning with three G residues fold into a monomer conformation and are preferentially translated. Transcripts beginning with one G residue fold into a dimer conformation. Structural switching is mediated by mutually exclusion interactions between regions U5 (pink), SL1 (blue), the AUG region (green), and a host tRNA (purple).