The role of reactive oxygen species (ROS) in the pathogenesis of viral infections
Role of ROS in the pathogenesis of infection with the human immunodeficiency virus (HIV)
Attention will be focussed on three classes of viruses: (1) RNA viruses, (2) DNA viruses, and (3) retroviruses, with particular attention to influenza viruses, hepatitis B virus, and HIV as representative examples of these three classes, respectively.
For each type of virus, evidence for the following will be analyzed: (1) the effect of the virus on activation of phagocytic cells to release ROS and pro-oxidant cytokines such as tumor necrosis factor; (2) the effect of the virus on the pro-/antioxidant balance in host cells, including virally induced inhibition of antioxidant enzymes such as superoxide dismutase and virally induced increases in pro-oxidants such as nitric oxide; (3) effects of the redox state of the cell on the genetic composition of the virus as well as ROS-mediated release of host cell nuclear transcription factor-kappa-B, resulting in increased viral replication; and (4) efficacy of antioxidants as therapeutic agents in viral diseases of both animal models and patients.
Antioxidants, Selenium and Vitamin E
The association between viral disease and nutrition has long been thought to be due to effects on the host immune system. This theory suggests that when a host is malnourished, the immune system is compromised, and thus increased susceptibility to viral infection will occur. However, the virus itself may also be affected by the nutritional status of the host. We have demonstrated that a normally-benign strain of coxsackievirus B3 (CVB3/0) becomes virulent in either Se-deficient or vitamin E-deficient mice. Although the deficient animals are immunosuppressed, the virus itself is also altered. Six nucleotide changes were found in the virus that replicated in the deficient mice, and once these mutations occurred, even mice with normal nutrition became susceptible to disease. Thus, the nutritional status of the host was able to transform an avirulent virus into a virulent one due to genomic changes in the virus. We believe that a common mechanism of oxidative stress is the underlying cause of the genetic changes. Both vitamin E and Se act as antioxidants, and benign virus inoculated into GSH peroxidase (EC 1.11.1.9)-knockout mice will also convert to virulence due to genomic changes. Our work points to the importance of host nutrition during a viral disease, not only from the perspective of the host, but from the perspective of the viral pathogen as well.
Nutritional status of the host
The nutritional status of the host has long been associated with both severity and susceptibility to infectious disease. The accepted model system proposes that inadequate nutrition impairs the functioning of the immune system, thus resulting in increased susceptibility to infection. However, current work suggests that not only can the nutritional status of the host affect the immune response, but it can also affect the viral pathogen. In a mouse model, a benign strain of coxsackievirus B3 became virulent and caused myocarditis in selenium- and vitamin E-deficient mice. This change in pathogenicity was due to mutations in the viral genome, which changed an avirulent virus into a virulent one. Once these mutations occurred, even mice with normal nutriture developed disease from the mutated virus. These results suggest that the oxidative stress status of the host can have a profound influence on a viral pathogen.