**2. Structure and replicative cycle of HCV**

The structure of the HCV virion remains poorly characterized despite several substantial progress in biochemical and morphological studies, and most of the HCV proteins are now actively being pursued as antiviral targets. HCV, discovered in 1989, is a positive-sense, singlestranded RNA virus, approximately 9600 nt in length, which belongs to the Flaviviridae family (*Flavivirus* genus), also including many arthropod-borne human pathogens such as yellow fever virus, West Nile virus, and dengue virus. HCV has been classified by the World Health Organization (WHO) as an oncogenic virus [1]. HCV-RNA encodes a polyprotein that is cleaved by cellular and viral proteases into structural and nonstructural proteins, each with a specific function. The structural proteins include two envelope glycoproteins E1 and E2, which are targets of the host antibody response and are crucial for viral entry and fusion, and a core protein (C), which interacts with the viral genome to form the nucleocapsid. The nonstructural proteins P7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B form a complex with the RNA of the virus to initiate viral replication, which occurs by budding through intracellular membranes. Mature virions are released into the extracellular milieu by exocytosis, and nascent virions incorporate cellular lipoproteins and apolipoproteins (e.g., apoE and apoB) as lipoviral particles [2]. HCV specifically infects hepatocytes, entering the cells by receptor-mediated endocytosis. During primary infection, HCV particles are transported by the blood stream and come in contact with hepatocytes after spanning the fenestrated endothelium of the liver sinusoids. In the Disse space, virions are in direct contact with the basolateral surface of hepatocytes that interact with multiple cell surface molecules, including attachment factors and receptors. Upon cell surface attachment, the subsequent steps of HCV entry are only partially known, but a putative mechanism has been described in analogy with other Flavi‐ viridae [3]. The virus/receptor complex is internalized, and the nucleocapsid is released into the cytoplasm, decapsidated, and the free viral RNA is used for both polyprotein translation and replication in the cytoplasm. Replication and posttranslational processing seem to take place in a membranous site constituted by viral nonstructural proteins and host cell proteins, the *replication complex*, located in close contact with the perinuclear membranes. Genome encapsidation presumably takes place in the endoplasmic reticulum, and nucleocapsids are enveloped and matured into the Golgi apparatus before the release of new virions in the extracellular space by exocytosis [4]. There are seven main known genotypes (GT) of HCV (from GT-1 to GT-7) that have been classified into 67 subtypes with distinct geographic distributions, modality of transmission, and sensitivity to interferon-based treatments [5]. Estimates of genotype distribution within 98 countries show that the most widespread genotype is the GT-1 (46%), with the subtypes 1a and 1b that are the most common in the United States and in Europe, respectively. Afterward, there are the GT-3 (22%), frequent among drug users; the GT-2 (13%), mainly present in the Mediterranean area; and the GT-4 (13%), mainly present in Egypt and other Arabic countries. GT-7 is extremely rare, and the incidence and prevalence are not yet known [5]. These seven genotypes are responsible for 97% of all infections present worldwide [6]. Although there are no differences in the risk of cirrhosis among all genotypes, GT-3 and GT-1b are associated with increased rate of hepatic steatosis and of hepatocellular carcinoma, respectively [7]. In addition, all these genotypes show different frequencies of polymorphisms associated with resistance to several classes of virustargeting drugs [8].
