Acceleration of viral replication and up-regulation of cytokine levels by antimalarials: implications in malaria-endemic areas.

Abstract

Abstract. Antimalarial drugs are widely used in malaria endemic areas, both for chemoprophylaxis and also empirically to treat patients presenting with fever. Previously, we have reported that chloroquine enhances the severity of Semliki forest virus (SFV) and encephalomyocarditis virus infection. The studies presented herein show that a broad spectrum of antimalarial drugs augmented the replication of SFV in mice, concomitant with greater tissue damage and up-regulation of mRNA levels of various inflammatory cytokine genes, including interleukin-1 receptor antagonist (IL-1Ra), IL-1␣, IL-1␤, IL-6, IL-12p40, and interferon-␥ inducing factor. Furthermore, chloroquine enhances IL-1Ra production in RAW cells in vitro. Since IL-1Ra is known to be up-regulated in a number of viral infections, we propose that a further enhancement of its expression by antimalarials may be responsible for the increased severity of viral infection in our studies. Thus, the widespread use of antimalarials in malaria-endemic areas may predispose the population to viral infections. Further studies are in progress to delineate mechanism(s) involved in cytokine up-regulation and acceleration of viral replication.Cytokines are important mediators in inflammatory pathology of the central nervous system (CNS), including encephalitides and demyelinating diseases such as multiple sclerosis.1 Interleukin-1 (IL-1) is an important cytokine implicated in the host response to injury and infection. 2 The production, secretion, and biologic response of IL-1 is tightly regulated, and a naturally occurring inhibitor, IL-1 receptor antagonist (IL-1Ra), has been demonstrated to prevent binding of IL-1 to its receptor, thereby impairing its further biologic effects. 3 Although IL-1Ra is a competitive inhibitor of IL-1, binding to the receptors with high affinity, high quantities (10-100 times more IL-1Ra than IL-1) are required to abrogate the effects of IL-1. The balance between IL-1 and IL-1Ra probably influences the regulation of the host response, and onset and severity of the inflammatory reaction. In this regard, selective over-production of IL-1Ra could be detrimental to the host when mounting an immune response. Increased levels of IL-1Ra have been noted in a variety of viral infections. [4][5][6][7][8][9] However, the role of IL-1Ra in viral-host interactions has not been clearly elucidated.We have previously shown that chloroquine enhances the severity of symptoms and mortality following Semliki forest virus (SFV) and encephalomyocarditis virus (EMCV) infection, along with an increase in viral titers in various organs.

Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries

“…Data of chloroquine against chikungunya virus is even more intriguing. While chloroquine had satisfactory antiviral activity against chikungunya in vitro, animal studies showed increase in virus replication, aggravation of fever and incomplete viral clearance [34]. Human trials of chloroquine showed no improvement in chikungunya acute illness and rather an increase in chronic arthralgia was observed during post-illness period, compared to the controls [35].…”

Hydroxychloroquine is associated with slower viral clearance in clinical COVID-19 patients with mild to moderate disease: A retrospective study

“…The time to SARS-CoV-2 negativity test was significantly longer in patients who received HCQ compared to those who did not receive the treatment (17 [13][14][15][16][17][18][19][20][21] vs. 10 [4][5][6][7][8][9][10][11][12][13] days, p=0.023, Figure 1). The time to negativity test was not significantly different between patients with symptoms and without symptoms (14 [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] vs. 15 [4][5][6][7][8][9][10][11][12][13][14][15][16][17]…”

Chloroquine mediated molecular tuning of astrocytes for enhanced permissiveness to HIV infection

“…Chloroquine (10–25 μM) has been shown to confer a weak anti-HIV activity outside the range of physiological concentrations by disrupting the glycosylation of gp120 (Rayne et al, 2004; Naarding et al, 2007). None the less, some reports have demonstrated no beneficial effect of chloroquine and instead have shown increased HIV infection in vitro and a more severe form of disease outcome in brain with upregulation of viral replication of other neurotropic viruses (Kamya et al, 2001; Seth et al, 1999). Given their high endocytic activity for HIV particles (Clarke et al, 2006; Deiva et al, 2006), in the present study we investigated the impact of chloroquine on HIV infection in neuro-glial cells.…”