To demonstrate that this property can explain the antiviral effect, we studied, on a cellular model of virus production, three molecules with the same effect: nitazoxanide and two others, one of which being structurally very different. The number of viruses produced and their infectious power were determined (figure). Since the results obtained with each of the three drugs are similar, only the level of impact on cellular respiration counts and not the nature of the drug (X axis of the figure): with a low (25%) or medium (50%) level of impact but not affecting cell viability, virus production remains normal or almost normal (red curve), while their infectious power decreases sharply (black curve). Stimulation of lactic fermentation (an emergency energy pathway if respiration is failing) restores the infectious power of viruses, thus confirming the critical role of available energy.

This observation would provide a simple explanation for the antiviral effect of nitazoxanide. The production of viral particles and their maturation into infectious viruses are two processes whose priority is shown by the shape of their response curve to a gradual decrease in energy resources (red vs. black in the figure). Replication follows markers of cellular vitality (division, survival) and therefore makes the best use of the host cell. But in the context of limited energy resources, the high sensitivity of the infectious power would protect the host from an amplification of the infection whose energy cost would become fatal for both partners. This example shows that the dependence of normal or pathological cellular processes on the energy state deserves attention and also that an adverse effect on cellular respiration (generally considered an undesirable effect of a drug) could also constitute the basis of a therapeutic intervention.

Legend:
Virus-producing cells are cultured in the presence of one of the three drugs with dosages causing a decrease in energy production by respiration of 25, 50, or 75% (X axis). Complete inhibition (100%) is obtained with a specific inhibitor. The point for X=0 represents cells treated with the common solvent. Y axis: the results are expressed in relation to the control (result obtained with untreated cells), in red the number of virus copies released into the medium (measured by PCR) and in black the infectivity of the viruses (revealed by the expression in its target cells of a fluorescent protein encoded by the genome of the virus). The significance of the difference with the solvent (X=0) is indicated * p<0.05, **** p<0.0001.