Anti-HIV effects of chloroquine: mechanisms of inhibition and spectrum of activity

Savarino, Andrea; Gennero, Luisa; Chen, Hou Chu; Serrano, Davide; Malavasi, Fabio; Boelaert, Johan R.; Sperber, Kirk

doi:10.1097/00002030-200111230-00002

Cited by 109 publications

(123 citation statements)

References 27 publications

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“…CQ is relatively inexpensive, is widely available, and has been shown to inhibit HIV-1 replication by disrupting the formation of glycoproteins in the viral envelope resulting in a broad spectrum of antiviral activity (Tsai et al, 1990;Savarino et al, 2001a). In keeping with previous reports (Savarino et al, 2001a), we found that CQ exhibited anti-HIV activity.…”

Section: Discussionsupporting

confidence: 89%

“…CQ suppresses HIV-1 and -2 replication in vitro (Tsai et al, 1990;Savarino et al, 2001a) (as does its analog hydroxyCQ; Sperber et al, 1997;Boelaert et al, 2001), possibly by inhibition of HIV gp120 (Tsai et al, 1990). In vitro studies examining CQ in HIV-infected cells has shown some additivity with zidovudine (Boelaert et al, 2001) and synergy with numerous protease inhibitors (PIs) in T cell lines (Savarino et al, 2004).…”

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confidence: 99%

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In Vitro Synergy and Enhanced Murine Brain Penetration of Saquinavir Coadministered with Mefloquine

Owen

Janneh²,

Hartkoorn³

et al. 2005

J Pharmacol Exp Ther

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Highly active antiretroviral therapy has substantially improved prognosis in human immunodeficiency virus (HIV). However, the integration of proviral DNA, development of viral resistance, and lack of permeability of drugs into sanctuary sites (e.g., brain and lymphocyte) are major limitations to current regimens. Previous studies have indicated that the antimalarial drug chloroquine (CQ) has antiviral efficacy and a synergism with HIV protease inhibitors. We have screened a panel of antimalarial compounds for activity against HIV-1 in vitro. A limited efficacy was observed for CQ, mefloquine (MQ), and mepacrine (MC). However, marked synergy was observed between MQ and saquinavir (SQV), but not CQ in U937 cells.Furthermore, enhancement of the antiviral activity of SQV and four other protease inhibitors (PIs) by MQ was observed in MT4 cells, indicating a class specific rather than a drug-specific phenomenon. We demonstrate that these observations are a result of inhibition of multiple drug efflux proteins by MQ and that MQ also displaces SQV from orosomucoid in vitro. Finally, coadministration of MQ and SQV in CD-1 mice dramatically altered the tissue distribution of SQV, resulting in a Ͼ3-fold and Ͼ2-fold increase in the tissue/blood ratio for brain and testis, respectively. This pharmacological enhancement of in vitro antiviral activity of PIs by MQ now warrants further examination in vivo.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

In Vitro Synergy and Enhanced Murine Brain Penetration of Saquinavir Coadministered with Mefloquine

Owen

Janneh²,

Hartkoorn³

et al. 2005

J Pharmacol Exp Ther

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“…Until the emergence of drug-resistant parasites, these drugs were the most effective means to treat malaria, a disease that claims 1 to 3 million lives annually (Foley and Tilley, 1998). In addition to malaria, quinoline-containing and structurally related compounds have been used in the treatment of lupus erythematosus (Van Beek and Piette, 2001), arthritis (Fox, 1993), and HIV (Savarino et al, 2001) and have been shown to exhibit antiprion activity (Korth et al, 2001). Remarkably, there is no clear mechanism known for the therapeutic action of these drugs in any of these diseases.…”

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confidence: 99%

Discovery of Novel Targets of Quinoline Drugs in the Human Purine Binding Proteome

et al. 2002

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The quinolines have been used in the treatment of malaria, arthritis, and lupus for many years, yet the precise mechanism of their action remains unclear. In this study, we used a functional proteomics approach that exploited the structural similarities between the quinoline compounds and the purine ring of ATP to identify quinoline-binding proteins. Several quinoline drugs were screened by displacement affinity chromatography against the purine binding proteome captured with ␥-phosphate-linked ATP-Sepharose. Screening of the human red blood cell purine binding proteome identified two human proteins, aldehyde dehydrogenase 1 (ALDH1) and quinone reductase 2 (QR2). In contrast, no proteins were detected upon screening of the Plasmodium falciparum purine binding proteome with the quinolines. In a complementary approach, we passed cell lysates from mice, red blood cells, or P. falciparum over hydroxychloroquine-or primaquine-Sepharose. Consistent with the displacement affinity chromatography screen, ALDH and QR2 were the only proteins recovered from mice and human red blood cell lysate and no proteins were recovered from P. falciparum. Furthermore, the activity of QR2 was potently inhibited by several of the quinolines in vitro. Our results show that ALDH1 and QR2 are selective targets of the quinolines and may provide new insights into the mechanism of action of these drugs.

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“…In vitro inhibition of HIV-1 replication in cultured peripheral blood lymphocytes has been observed only at CQ concentrations from 3 to 10 M (8, 10). This inhibition is associated with alterations in gp120 glycosylation (10). Nevertheless, such high CQ concentrations are toxic to peripheral blood lymphocytes (8) (data not shown).…”

mentioning

confidence: 99%

The Ability of Chloroquine To Prevent Tat-Induced Cytokine Secretion by Monocytes Is Implicated in Its In Vivo Anti-Human Immunodeficiency Virus Type 1 Activity

Rayne

Vendeville

Bonhoure

et al. 2004

J Virol

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Hydroxychloroquine at 1 M reduces the load of human immunodeficiency virus type 1 (HIV-1) in patients, whereas chloroquine (CQ) concentrations above 3 M are required for inhibition of HIV-1 replication in peripheral blood mononuclear cells. Exogenous HIV-1 Tat reaches the cytosol of T cells by using low endosomal pH, and endosome neutralization by CQ prevents Tat from entering and affecting T cells. We show here that 0.6 M CQ inhibits cytokine secretion induced by Tat in monocytes without affecting lipopolysaccharidetriggered cytokine release. This finding suggests that the in vivo anti-HIV-1 effect of CQ results not from a direct effect on the infected cell but rather from the capacity of CQ to prevent Tat from perturbing the cytokine balance.

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Anti-HIV effects of chloroquine: mechanisms of inhibition and spectrum of activity

Abstract: At clinically achievable concentrations chloroquine inhibits HIV-1 post-integrationally by affecting newly produced viral envelope glycoproteins, and the drug has broad-spectrum anti-HIV-1 and HIV-2 activity.

Cited by 109 publications

References 27 publications

In Vitro Synergy and Enhanced Murine Brain Penetration of Saquinavir Coadministered with Mefloquine

In Vitro Synergy and Enhanced Murine Brain Penetration of Saquinavir Coadministered with Mefloquine

Discovery of Novel Targets of Quinoline Drugs in the Human Purine Binding Proteome

The Ability of Chloroquine To Prevent Tat-Induced Cytokine Secretion by Monocytes Is Implicated in Its In Vivo Anti-Human Immunodeficiency Virus Type 1 Activity

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