Abstract
Previous studies have indicated that viruses can interact with mitochondria and affect their function. Further, emerging data now show that many more viruses may influence the mitochondrial pathway of apoptosis and thus there is widespread potential for interaction with the respiratory chain in this organelle. Such interactions could have consequences for the clinical outcome of persistent infections; however it is not known how widespread effects on respiration may be. We have therefore screened different human viruses for an effect on the mitochondrial respiration. We found that human herpes virus type one (HHV-1) and influenza virus (IV) caused a profound decrease in total cell respiration whilst measles virus (MV) and cytomegalovirus (CMV) did not. We have further analysed the integrity of the electron transport chain in the mitochondria of HHV-infected HeLa cells and located a block at complex II; electrons donated to this complex were unable to flow on to complex EL Further investigation revealed that this block was established during the beta phase of HHV-1 protein synthesis. Beta-phase proteins were assessed for potential involvement in this process using the reported literature and a shortlist of candidates was derived. Of these the beta protein Us3 was cloned and expressed by transfection and was found to induce respiratory block in comparison with mock-transfected and luciferase-transfected cells. A mutant deficient in this protein was obtained and shown to be unable of inducing a similar effect. We thus conclude that taxonomically distinct viruses can indeed affect mitochondrial function and virus- specified proteins are responsible. In the case of herpes virus, HHV-1 protein US3 is capable of inducing this effect alone; no other virus proteins are required. Furthermore US3 appears to be the only HHV-1 protein capable of inducing this effect. These findings demonstrate that diverse viruses may induce mitochondrial impairment and this could be a widespread phenomenon. This could underlie the induction of similar features of infection by different viruses and could be significant in the context of a persistent infection.