Effects of chloroquine on viral infections: an old drug against today's diseases?

Abstract

Chloroquine is a 9-aminoquinoline known since 1934. Apart from its well-known antimalarial effects, the drug has interesting biochemical properties that might be applied against some viral infections. Chloroquine exerts direct antiviral effects, inhibiting pH-dependent steps of the replication of several viruses including members of the flaviviruses, retroviruses, and coronaviruses. Its best-studied effects are those against HIV replication, which are being tested in clinical trials. Moreover, chloroquine has immunomodulatory effects, suppressing the production/release of tumour necrosis factor alpha and interleukin 6, which mediate the inflammatory complications of several viral diseases. We review the available information on the effects of chloroquine on viral infections, raising the question of whether this old drug may experience a revival in the clinical management of viral diseases such as AIDS and severe acute respiratory syndrome, which afflict mankind in the era of globalisation.

Figure 1

Steps of the replication of different viruses affected by chloroquine (marked by red rectangles). Chloroquine inhibits the replication of different viruses either at the early or late stages of viral replication.

Figure 2

Effects of chloroquine on the immune system. TNFα is produced by activated monocytes/macrophages. Among its multiple functions it helps to activate resting monocytes and favours extravasation of neutrophils by opening tight junctions between human vascular endothelial cells and upregulating leucoyte adhesion molecules (LAM). Chloroquine diminishes TNFα production and downregulates the TNFα receptors 1 and 2 (TNFR) on the monocyte cell surface, which eventually results in decreasedmonocyte activation as well as decreased leucocyte extravasation. Red crosses mark the steps directly inhibited by chloroquine.

Figure 3

Hypothetical model for the potential effects of chloroquine (CQ) on the immunopathogenesis of severe acute respiratory syndrome (SARS). Proinflammatory cytokines are thought to be important in acute respiratory distress syndrome (ARDS). We hypothesise that chloroquine (black arrow), by inhibiting TNFα and interleukin 6 (IL6) production, might block the subsequent cascade of events, which leads to ARDS.