New insights into the antiviral effects of chloroquineписьмо
Аннотация: In a paper published 2 years ago in this journal, some of us described the potentially therapeutic benefits of the quinoline antimalarial chloroquine in viral diseases such as HIV-1/AIDS and severe acute respiratory syndrome (SARS).1Savarino A Boelaert JR Cassone A Majori G Cauda R Effects of chloroquine on viral infections: an old drug against today's diseases?.Lancet Infect Dis. 2003; 3: 722-727Summary Full Text Full Text PDF PubMed Scopus (975) Google Scholar Chloroquine/hydroxychloroquine has since been adopted to treat HIV-1-infected patients in clinical trials, and new insights into its antiviral activity have been obtained from in-vitro studies. On the HIV/AIDS front, chloroquine (250 mg twice daily) has been administered to HIV-1-infected patients with baseline viral loads over 50 000 copies per mL, in combination with lamivudine (150 mg twice daily) and hydroxyurea (500 mg twice daily) in an ongoing clinical trial in India.2Joshi SR Butala N Patwardhan MR Daver NG Kelkar D Low cost anti-retroviral options: chloroquine based ARV regimen combined with hydroxyurea and lamivudine: a new economical triple therapy.J Assoc Phys India. 2004; 52: 597-598PubMed Google Scholar Ten out of 18 volunteers had an undetectable viral load at week 24.2Joshi SR Butala N Patwardhan MR Daver NG Kelkar D Low cost anti-retroviral options: chloroquine based ARV regimen combined with hydroxyurea and lamivudine: a new economical triple therapy.J Assoc Phys India. 2004; 52: 597-598PubMed Google Scholar The median drop in viral load was more than 2·0 log,2Joshi SR Butala N Patwardhan MR Daver NG Kelkar D Low cost anti-retroviral options: chloroquine based ARV regimen combined with hydroxyurea and lamivudine: a new economical triple therapy.J Assoc Phys India. 2004; 52: 597-598PubMed Google Scholar more than the median 1·5 log drop seen with a nucleoside reverse transcriptase inhibitor (NRTI) and hydroxyurea alone.3Lori F Foli A Groff A et al.Optimal suppression of HIV replication by low-dose hydroxyurea through the combination of antiviral and cytostatic ('virostatic') mechanisms.AIDS. 2005; 19: 1173-1181Crossref PubMed Scopus (26) Google Scholar These results are different from those of another trial in Singapore using didanosine (125–250 mg twice daily), hydroxyurea (500 mg twice daily), and hydroxychloroquine (200 mg twice daily, corresponding to 125 mg of chloroquine).1Savarino A Boelaert JR Cassone A Majori G Cauda R Effects of chloroquine on viral infections: an old drug against today's diseases?.Lancet Infect Dis. 2003; 3: 722-727Summary Full Text Full Text PDF PubMed Scopus (975) Google Scholar The median drop in viral load was 1·3 log, similar to that induced by a NRTI plus hydroxyurea. Follow-up of these patients at week 144 suggests that the value of hydroxychloroquine may lie in the maintenance of the effects of didanosine/hydroxyurea.4Paton NI Aboulhab J Hydroxychloroquine, hydroxyurea and didanosine as initial therapy for HIV-infected patients with low viral load: safety, efficacy and resistance profile after 144 weeks.HIV Med. 2005; 6: 13-20Crossref PubMed Scopus (47) Google Scholar The discrepancy between the two studies, besides differences in the design and patients enrolled, probably reflects the different dosages of chloroquine/hydroxychloroquine. Drops in viral load are reported to occur using daily doses of 800 mg of hydroxychloroquine,1Savarino A Boelaert JR Cassone A Majori G Cauda R Effects of chloroquine on viral infections: an old drug against today's diseases?.Lancet Infect Dis. 2003; 3: 722-727Summary Full Text Full Text PDF PubMed Scopus (975) Google Scholar corresponding to 500 mg of chloroquine (as used in the Indian study), but not using 250 mg of chloroquine daily,5Luchters SMF, Veldhuijzen NJ, Nsanzabera D. et al. A phase I/II randomised placebo controlled study to evaluate chloroquine administration to reduce HIV-1 RNA in breast milk in an HIV-1 infected breastfeeding population: the CHARGE Study. XV International Conference on AIDS; Bangkok, Thailand; July 11–16, 2004. Abstract TuPeB4499.Google Scholar corresponding to 400 mg of hydroxychloroquine (as adopted in the Singapore study). Chloroquine/hydroxychloroquine might thus be a valuable option to be tested in low-cost antiretroviral combinations, but correct dosages should be used, considering that the study participants should be regularly monitored to prevent retinopathy. Prospective randomised double-blind placebo studies are also needed to assess the contribution of chloroquine/hydroxychloroquine as part of an antiretroviral regimen. According to new in-vitro results, the antiretroviral effects of chloroquine are attributable to the inhibition of viral particle glycosylation.6Savarino A Lucia MB Rastrelli E et al.Anti-HIV effects of chloroquine: inhibition of viral particle glycosylation and synergism with protease inhibitors.J Acquir Immune Defic Syndr. 1996; 35: 223-232Crossref Scopus (111) Google Scholar These effects appeared to be specific, since the chloroquine concentrations effective in vitro neither affected any other step in HIV-1 replication nor were cytotoxic.6Savarino A Lucia MB Rastrelli E et al.Anti-HIV effects of chloroquine: inhibition of viral particle glycosylation and synergism with protease inhibitors.J Acquir Immune Defic Syndr. 1996; 35: 223-232Crossref Scopus (111) Google Scholar Our hypothesis that chloroquine might inhibit replication of the SARS coronavirus1Savarino A Boelaert JR Cassone A Majori G Cauda R Effects of chloroquine on viral infections: an old drug against today's diseases?.Lancet Infect Dis. 2003; 3: 722-727Summary Full Text Full Text PDF PubMed Scopus (975) Google Scholar has been confirmed in two independent in-vitro studies.7Keyaerts E Vijgen L Maes P Neyts J Van Ranst M In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine.Biochem Biophys Res Commun. 2004; 323: 264-268Crossref PubMed Scopus (526) Google Scholar, 8Vincent MJ Bergeron E Benjannet S et al.Chloroquine is a potent inhibitor of SARS coronavirus infection and spread.Virol J. 2005; 2: 69Crossref PubMed Scopus (1395) Google Scholar Researchers at the Belgian Catholic University of Leuven found that chloroquine inhibited SARS coronavirus replication with a 50% effective concentration of 8·8 (SE 1·2) μmol/L, within the range of blood concentrations achievable during antimalarial treatment.7Keyaerts E Vijgen L Maes P Neyts J Van Ranst M In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine.Biochem Biophys Res Commun. 2004; 323: 264-268Crossref PubMed Scopus (526) Google Scholar The dose inducing 50% cytostatic activity was much higher (261·3 [14·5] μmol/L). Time-of-addition experiments indicated that chloroquine affected an early stage of SARS coronavirus replication.7Keyaerts E Vijgen L Maes P Neyts J Van Ranst M In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine.Biochem Biophys Res Commun. 2004; 323: 264-268Crossref PubMed Scopus (526) Google Scholar Researchers at the Centers for Disease Control and Prevention (Atlanta, GA, USA) reported potent anti-SARS coronavirus effects of chloroquine in vitro, attributable to a deficit in the glycosylation of the SARS coronavirus receptor ACE2.8Vincent MJ Bergeron E Benjannet S et al.Chloroquine is a potent inhibitor of SARS coronavirus infection and spread.Virol J. 2005; 2: 69Crossref PubMed Scopus (1395) Google Scholar Again, the antiviral drug concentrations were not cytotoxic. If animal models confirm these results, chloroquine might represent a valuable therapeutic option if SARS re-emerges. The broad spectrum antiviral effects of chloroquine deserve particular attention in a time in which the world is threatened by the possibility of a new influenza pandemic, and the availability of effective drugs would be fundamental during evaluation of an effective vaccine. The effect of chloroquine against replication of Orthomyxoviridae has long been known.9Miller DK Lenard J Antihistaminics, local anesthetics, and other amines as antiviral agents.Proc Natl Acad Sci USA. 1981; 78: 3605-3609Crossref PubMed Scopus (70) Google Scholar, 10Shibata M Aoki H Tsurumi T et al.Mechanism of uncoating of influenza B virus in MDCK cells: action of chloroquine.J Gen Virol. 1983; 64: 1149-1156Crossref PubMed Scopus (55) Google Scholar Inhibitory effects of chloroquine on both type A and B influenza viruses have been described.9Miller DK Lenard J Antihistaminics, local anesthetics, and other amines as antiviral agents.Proc Natl Acad Sci USA. 1981; 78: 3605-3609Crossref PubMed Scopus (70) Google Scholar, 10Shibata M Aoki H Tsurumi T et al.Mechanism of uncoating of influenza B virus in MDCK cells: action of chloroquine.J Gen Virol. 1983; 64: 1149-1156Crossref PubMed Scopus (55) Google Scholar We are currently investigating the inhibitory effect of chloroquine on the H5N9/A/chicken/Italy/9097/97 avian influenza virus, recently isolated from poultry in Italy.11Donatelli I Campitelli L Di Trani L et al.Characterization of H5N2 influenza viruses from Italian poultry.J Gen Virol. 2001; 82: 623-630Crossref PubMed Scopus (54) Google Scholar Depending on the viral challenging doses and the methods adopted to detect the antiviral effects, the inhibitory concentrations fell within the 0·5–10 μmol/L range—ie, clinically achievable in plasma during malaria treatment (LDT, AS, ID, RC, and AC, unpublished data). If these effects are confirmed, chloroquine would deserve to be tested against the H5N1 type A avian influenza virus, currently a matter of serious concern for public health. As discussed above, glycosylation inhibition might represent a major mechanism for the antiviral effects of chloroquine, suggesting that specific interactions of chloroquine with sugar-modifying enzymes or glycosyltransferases may occur within human cells (figure). Chloroquine was recently shown to inhibit quinone reductase 2,13Kwiek JJ Haystead TA Rudolph J Kinetic mechanism of quinone oxidoreductase 2 and its inhibition by the antimalarial quinolines.Biochemistry. 2004; 43: 4538-4547Crossref PubMed Scopus (118) Google Scholar a structural neighbour of UDP-N-acetylglucosamine 2-epimerases,14National Center for Biotechnology InformationMMDB—Entrez's Structure Database.http://www.ncbi.nlm.nih.gov/Structure/MMDB/mmdb.shtmlGoogle Scholar which are involved in sialic acid biosynthesis. If chloroquine should indeed inhibit the biosynthesis of sialic acid, this effect could explain not only the effects of chloroquine on HIV and SARS coronavirus (sialic acid moieties are present in HIV-1 glycoproteins and SARS coronavirus receptor ACE2), but also the in-vitro effects on orthomyxoviruses (which use sialic acid moieties as receptors15Olofsson S Kumlin U Dimock K Arnberg N Avian influenza and sialic acid receptors: more than meets the eye?.Lancet Infect Dis. 2005; 5: 184-188Summary Full Text Full Text PDF PubMed Scopus (75) Google Scholar). These effects deserve further investigation, in that they may lead to new strategies controlling the replication of several viruses. ErratumSavarino A, Di Trani L, Donatelli I, Cauda R, Cassone A. New insights into the antiviral effects of chloroquine. Lancet Infect Dis 2006; 6: 67–69. Reference 6 should read "Savarino A, Lucia MB, Rastrelli E, et al. Anti-HIV effects of chloroquine: inhibition of viral particle glycosylation and synergism with protease inhibitors. J Acquir Immune Defic Syndr 2004; 35: 223–32." Full-Text PDF
Год издания: 2006
Издательство: Elsevier BV
Источник: The Lancet Infectious Diseases
Ключевые слова: interferon and immune responses, Drug-Induced Ocular Toxicity, Retinoids in leukemia and cellular processes
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Том: 6
Выпуск: 2
Страницы: 67–69