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Paradoxical Effect of Chloroquine Treatment in Enhancing Chikungunya Virus Infection.
Viruses. 2018 05 17; 10(5)V

Abstract

Since 2005, Chikungunya virus (CHIKV) re-emerged and caused numerous outbreaks in the world, and finally, was introduced into the Americas in 2013. The lack of CHIKV-specific therapies has led to the use of non-specific drugs. Chloroquine, which is commonly used to treat febrile illnesses in the tropics, has been shown to inhibit CHIKV replication in vitro. To assess the in vivo effect of chloroquine, two complementary studies were performed: (i) a prophylactic study in a non-human primate model (NHP); and (ii) a curative study "CuraChik", which was performed during the Reunion Island outbreak in 2006 in a human cohort. Clinical, biological, and immunological data were compared between treated and placebo groups. Acute CHIKV infection was exacerbated in NHPs treated with prophylactic administration of chloroquine. These NHPs displayed a higher viremia and slower viral clearance (p < 0.003). Magnitude of viremia was correlated to the type I IFN response (Rho = 0.8, p < 0.001) and severe lymphopenia (Rho = 0.8, p < 0.0001), while treatment led to a delay in both CHIKV-specific cellular and IgM responses (p < 0.02 and p = 0.04, respectively). In humans, chloroquine treatment did not affect viremia or clinical parameters during the acute stage of the disease (D1 to D14), but affected the levels of C-reactive Protein (CRP), IFNα, IL-6, and MCP1 over time (D1 to D16). Importantly, no positive effect could be detected on prevalence of persistent arthralgia at Day 300. Although inhibitory in vitro, chloroquine as a prophylactic treatment in NHPs enhances CHIKV replication and delays cellular and humoral response. In patients, curative chloroquine treatment during the acute phase decreases the levels of key cytokines, and thus may delay adaptive immune responses, as observed in NHPs, without any suppressive effect on peripheral viral load.

Authors+Show Affiliations

Immunology of Viral Infections and Autoimmune Diseases (IMVA), IDMIT Department, Institut de Biologie François-Jacob (IBJF), Univ. Paris-Sud⁻INSERM U1184, CEA, 92265 Fontenay-aux-Roses, France. pierre.roques@cea.fr.IRD, INSERM U1207, EHESP French School of Public Health, UMR190, Aix-Marseille University, 13005 Marseille, France. djamt@yahoo.fr.Immunology of Viral Infections and Autoimmune Diseases (IMVA), IDMIT Department, Institut de Biologie François-Jacob (IBJF), Univ. Paris-Sud⁻INSERM U1184, CEA, 92265 Fontenay-aux-Roses, France. laurdupuis@gmail.com.Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis 138648, Singapore. Lum_Fok_Moon@immunol.a-star.edu.sg.Immunology of Viral Infections and Autoimmune Diseases (IMVA), IDMIT Department, Institut de Biologie François-Jacob (IBJF), Univ. Paris-Sud⁻INSERM U1184, CEA, 92265 Fontenay-aux-Roses, France. klabadie@genoscope.cns.fr.Immunology of Viral Infections and Autoimmune Diseases (IMVA), IDMIT Department, Institut de Biologie François-Jacob (IBJF), Univ. Paris-Sud⁻INSERM U1184, CEA, 92265 Fontenay-aux-Roses, France. frederic.martinon@cea.fr.Immunology of Viral Infections and Autoimmune Diseases (IMVA), IDMIT Department, Institut de Biologie François-Jacob (IBJF), Univ. Paris-Sud⁻INSERM U1184, CEA, 92265 Fontenay-aux-Roses, France. gabriel.gras@cea.fr.Service de Virologie, AP-HP, Hôpital Cochin, Paris Descartes University, 75014 Paris, France. pflebon2@wanadoo.fr.Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis 138648, Singapore. lisa_ng@immunol.a-star.edu.sg.IRD, INSERM U1207, EHESP French School of Public Health, UMR190, Aix-Marseille University, 13005 Marseille, France. xavier.de-lamballerie@univ-amu.fr.Immunology of Viral Infections and Autoimmune Diseases (IMVA), IDMIT Department, Institut de Biologie François-Jacob (IBJF), Univ. Paris-Sud⁻INSERM U1184, CEA, 92265 Fontenay-aux-Roses, France. roger.le-grand@cea.fr.

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29772762

Citation

Roques, Pierre, et al. "Paradoxical Effect of Chloroquine Treatment in Enhancing Chikungunya Virus Infection." Viruses, vol. 10, no. 5, 2018.
Roques P, Thiberville SD, Dupuis-Maguiraga L, et al. Paradoxical Effect of Chloroquine Treatment in Enhancing Chikungunya Virus Infection. Viruses. 2018;10(5).
Roques, P., Thiberville, S. D., Dupuis-Maguiraga, L., Lum, F. M., Labadie, K., Martinon, F., Gras, G., Lebon, P., Ng, L. F. P., de Lamballerie, X., & Le Grand, R. (2018). Paradoxical Effect of Chloroquine Treatment in Enhancing Chikungunya Virus Infection. Viruses, 10(5). https://doi.org/10.3390/v10050268
Roques P, et al. Paradoxical Effect of Chloroquine Treatment in Enhancing Chikungunya Virus Infection. Viruses. 2018 05 17;10(5) PubMed PMID: 29772762.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Paradoxical Effect of Chloroquine Treatment in Enhancing Chikungunya Virus Infection. AU - Roques,Pierre, AU - Thiberville,Simon-Djamel, AU - Dupuis-Maguiraga,Laurence, AU - Lum,Fok-Moon, AU - Labadie,Karine, AU - Martinon,Frédéric, AU - Gras,Gabriel, AU - Lebon,Pierre, AU - Ng,Lisa F P, AU - de Lamballerie,Xavier, AU - Le Grand,Roger, Y1 - 2018/05/17/ PY - 2018/04/25/received PY - 2018/05/11/revised PY - 2018/05/12/accepted PY - 2018/5/19/entrez PY - 2018/5/19/pubmed PY - 2018/11/28/medline KW - alphavirus KW - chikungunya KW - chloroquine KW - macaque KW - monocyte-macrophage JF - Viruses JO - Viruses VL - 10 IS - 5 N2 - Since 2005, Chikungunya virus (CHIKV) re-emerged and caused numerous outbreaks in the world, and finally, was introduced into the Americas in 2013. The lack of CHIKV-specific therapies has led to the use of non-specific drugs. Chloroquine, which is commonly used to treat febrile illnesses in the tropics, has been shown to inhibit CHIKV replication in vitro. To assess the in vivo effect of chloroquine, two complementary studies were performed: (i) a prophylactic study in a non-human primate model (NHP); and (ii) a curative study "CuraChik", which was performed during the Reunion Island outbreak in 2006 in a human cohort. Clinical, biological, and immunological data were compared between treated and placebo groups. Acute CHIKV infection was exacerbated in NHPs treated with prophylactic administration of chloroquine. These NHPs displayed a higher viremia and slower viral clearance (p < 0.003). Magnitude of viremia was correlated to the type I IFN response (Rho = 0.8, p < 0.001) and severe lymphopenia (Rho = 0.8, p < 0.0001), while treatment led to a delay in both CHIKV-specific cellular and IgM responses (p < 0.02 and p = 0.04, respectively). In humans, chloroquine treatment did not affect viremia or clinical parameters during the acute stage of the disease (D1 to D14), but affected the levels of C-reactive Protein (CRP), IFNα, IL-6, and MCP1 over time (D1 to D16). Importantly, no positive effect could be detected on prevalence of persistent arthralgia at Day 300. Although inhibitory in vitro, chloroquine as a prophylactic treatment in NHPs enhances CHIKV replication and delays cellular and humoral response. In patients, curative chloroquine treatment during the acute phase decreases the levels of key cytokines, and thus may delay adaptive immune responses, as observed in NHPs, without any suppressive effect on peripheral viral load. SN - 1999-4915 UR - https://www.unboundmedicine.com/medline/citation/29772762/full_citation L2 - https://www.mdpi.com/resolver?pii=v10050268 DB - PRIME DP - Unbound Medicine ER -