HSV is a double-stranded DNA virus, structurally composed of a linear genome packaged into an icosahedral capsid enclosed by tegument proteins and surrounded by a lipid bilayer membrane with embedded proteins and glycoproteins (envelope). Primary infection in humans usually occurs in the orofacial mucosa during childhood. There the virus replicates within the epithelial cells and undergoes its typical lytic life cycle ending with the production of infectious virions and lysis of the host cell. HSV entry into the host cell requires sequential interaction between specific viral membrane glycoproteins (gB, gC, gD, gH and gL) and cellular receptors [heparan sulphate proteoglycans (HSPG), nectin-1 and 2, herpesvirus entry mediator (HVEM) or 3-O sulphated heparan sulphate (3-OS HS)]. On entry, the nucleocapsid is transported to the nuclear membrane and the viral DNA is released into the nucleus for transcription of viral genes and replication. The HSV genome consists of two long structures of unique sequences (designated long (UL) and short (US)), that encode over 80 distinct genes, and it is transcribed by the RNA polymerase II of the infected host. Immediate-early genes are the first to be expressed following infection and they encode proteins that regulate the subsequent expression of early and late viral genes. Early gene expression then allows the synthesis of enzymes involved in DNA replication and the production of certain envelope glycoproteins. Expression of late genes occurs last; this group of genes predominantly encodes proteins that form the virus particle. This latter is then released from host cells by budding. HSV-1 is able to establish a lifelong latent infection in sensory neurons, particularly in cellular bodies of those feeding the site of primary infection [53]. This latency is characterized by the presence of a functional viral genome without production of the infectious virus. During this time, the latency-associated transcripts (LATs) are the only prominent transcripts [54] whose role in generating functional peptides or proteins is still a matter of debate [55]. Reactivation from latency can be triggered by several external stimuli (stress, immunosuppression, etc.) that activate viral gene expression. Newly produced virions are transported to the sites of primary infection where they cause recurrent herpetic lesions in some people. Interestingly, APOE4 is a risk factor for these recurrent herpetic lesions [56, 57]
Giovanna De Chiara, Maria Elena Marcocci, Rossella Sgarbanti, Livia Civitelli, Cristian Ripoli, Roberto Piacentini, Enrico Garaci, Claudio Grassi, Anna Teresa Palamara
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