Molecular Mechanisms and Clinical Manifestations of Persistent Viral Infections

Dear Colleagues,

Persistent viral infections are recognized as an important cause of morbidity and mortality in humans; in fact, they are also responsible for silent pandemics (e.g., HIV, HBV, and HCV) that cause several million deaths each year worldwide.

Many viruses can remain in the host for a long time, even life-long, after acute infection and establish persistence in different cell types that represent an important reservoir for dissemination of the virus in the environment and spread to other hosts associated with an asymptomatic manner, as well as symptomatic or paucisymptomatic clinical manifestations.

Several factors contribute to the establishment and maintenance of the persistence of a virus in the host, such as the absence of a cytopathic effect or the restriction of viral replication; the maintenance of the viral genome in host cells in extrachromosomal form (episome) or integrated into the cellular genome; and, most importantly, the ability to escape eradication of the virus by the immune system, associated with or with not the activation of the inflammatory response that may be a significant part of pathogenesis. There are three types of persistent virus–host infections: 1) chronic infection is characterized by the presence of the virus at a low viral load that can cause minimal continuous damage over time, leading to organ impairment and clinical manifestation of the disease (e.g., HBV, HCV); 2) latent infection in which the viral genome is maintained in the absence of the production of infectious viral particles and only after successive reactivations from the latent state (recurrent infections), which may occur at later times in the host's life, can the function of the target organ be compromised (e.g., keratoconjunctivitis from HSV); and 3) slow infection, which is characterized by a more extended incubation period followed by ongoing disease. Some viruses use this strategy to persist in the central nervous system (CNS), an immune-privileged site, and over time, following virus reactivation causes degenerative CNS disease (e.g., SSPE, Subacute Sclerosing PanEncephalitis from measles). Other viruses make an immune escape by infecting cells of the immune system, as in the case of HIV, in which the proviral DNA integrates into the cellular genome of lymphocytes and macrophages, where the virus establishes a slow infection that leads to AIDS many years later. For many RNA viruses able to establish persistent infections, the molecular mechanism by which the genome remains within host cells is still being studied (e.g., long-COVID-19 from SARS-CoV-2). In some cases of persistent infection, injury is not associated with the death of infected cells but rather with immune-mediated cellular damage (e.g., hepatitis from HBV, HCV). Oncogenic viruses establish persistent infections, most of which do not lead to direct carcinogenesis, and tumor-directed progression depends on other pro-cancerogenic factors (Burkitt lymphoma from EBV); in other cases, however, tumors are strictly dependent on the viral expression of oncoproteins (e.g., cervical cancer from HPV or Rous sarcoma from Rous sarcoma virus). The process of endogenization of the human genome consists of the acquisition by integration of viral sequences into the DNA of the germ line cells of our forefathers during the evolutionary process resulting from persistent infections with ancestral Retrovirus and, more recently, also observed for non-retroviral viruses, Bornavirus. Antiviral drugs are the most commonly used therapeutic modality to counteract persistent infections, although eradicating the virus is very challenging. An example of pharmacological success is the current anti-HCV drugs, which allow for the elimination of the virus in about 95% of infected individuals (e.g., Sofosbuvir for HCV cure). This Special Issue will present the most recent research on understanding the molecular mechanisms, clinical manifestations, and therapeutic strategies during persistent viral infections.

Research articles, reviews, and short communications are welcome. 

Dr. Anna Rosa Garbuglia
Dr. Simone La Frazia
Guest Editors

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