Villains or heroes? The raison d'être of viruses

Watanabe, Tokiko; Kawaoka, Yoshihiro

In traditional virology, most viruses found in humans are considered to be pathogenic to their hosts; however, recent studies have shown that there are some viruses that have symbiotic relationships with their hosts and do not cause disease. Infection with one virus may protect the host from a superinfection with another pathogen. Barton et al. 16 demonstrated that latent infection with the herpesviruses murine gammaherpesvirus 68 or murine cytomegalovirus, which are genetically related to the human pathogens Epstein-Barr virus and human cytomegalovirus, respectively, led to crossprotection in mice. Infection with these viruses induced prolonged production of the antiviral cytokine interferon-gamma and systemic activation of macrophages that protected the mice from subsequent bacterial infections with either Listeria monocytogenes or Yersinia pestis. 16 Moreover, it has been reported that superinfection with hepatitis A virus suppressed hepatitis C virus replication in patients with chronic hepatitis C in at least two cases, 17 and infection with human cytomegalovirus (HCMV) suppressed superinfection with HIV-1 in vitro as a result of the downregulation of the expression of CCR5, a co-receptor for HIV-1, induced by the HCMV infection. 18 Some viruses also have beneficial effects with respect to non-infectious diseases. Epidemiologic studies suggest that virus infections in childhood might confer protection against some cancers later in life. For example, the risk of chronic lymphoid leukaemia in subjects who had measles in childhood is relatively low, 19 and mumps infection in childhood might protect against the development of ovarian cancer in adults. 20 However, infection with oncoviruses is known to increase the risk of development of some cancers (e.g. cervical cancer and liver cancer induced by the human papillomavirus and hepatitis B virus/ hepatitis C virus infection, respectively). 21 Such information is important when considering strategies for cancer immunotherapy and/or vaccination campaigns. In addition, the infection of non-obese diabetic mice with lymphocytic choriomeningitis virus prevented the infected mice from developing autoimmune disease and subsequent type I diabetes (insulin-dependent diabetes mellitus). 22, 23 Chronic viral infection of mice with murine cytomegalovirus (CMV) increased epithelial turnover and wound repair via antiviral cytokine type I interferons (IFNs), 24 but CMV infection can promote cancer malignancy; this phenomenon is known as 'oncomodulation'. 25, 26 Recent metagenomic studies have revealed that virus infection sometimes confers benefits including the regulation of microbiota in the gut. Bacteriophages are abundant in the gut and are thought to modulate the gut microbiota by infecting specific bacterial populations. Accordingly, potential therapeutic applications of bacteriophages in humans (e.g. control of antibiotic-resistant bacteria, stabilisation of healthy gut microbes) have been considered. 27, 28 Therefore, the elucidation of the symbiotic effects of viruses on the physiological functions and immune responses of their hosts, as well as clarification of the functional mechanisms involved, will lead to an understanding of the essential roles of viruses in regulating the biological processes of their hosts.