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Research Article

Ivermectin Inhibits Zika Virus Replication in Vitro But Does Not Prevent Zika Virus Infection in Rhesus Macaques (Macaca mulatta)

Thomas S. Cotrone Department of Virology, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Science (WRAIR-AFRIMS), Bangkok, Thailand;

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Kevin Kobylinski Department of Entomology, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Science (WRAIR-AFRIMS), Bangkok, Thailand;

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Alongkot Ponlawat Department of Entomology, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Science (WRAIR-AFRIMS), Bangkok, Thailand;

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Rawiwan Im-Erbsin Department of Veterinary Medicine, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Science (WRAIR-AFRIMS), Bangkok, Thailand;

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Piyanate Sunyakumthorn Department of Veterinary Medicine, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Science (WRAIR-AFRIMS), Bangkok, Thailand;

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Pattaraporn Vanachayangkul Department of Bacterial and Parasitic Diseases, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Science (WRAIR-AFRIMS), Bangkok, Thailand

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Yongyuth Poolpanichupatam Department of Virology, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Science (WRAIR-AFRIMS), Bangkok, Thailand;

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Jindarat Lohachanakul Department of Virology, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Science (WRAIR-AFRIMS), Bangkok, Thailand;

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Chonticha Klungthong Department of Virology, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Science (WRAIR-AFRIMS), Bangkok, Thailand;

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Aaron Farmer Department of Virology, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Science (WRAIR-AFRIMS), Bangkok, Thailand;

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Stefan Fernandez Department of Virology, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Science (WRAIR-AFRIMS), Bangkok, Thailand;

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Taweewun Hunsawong Department of Virology, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Science (WRAIR-AFRIMS), Bangkok, Thailand;

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DOI:
https://doi.org/10.4269/ajtmh.24-0183
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Ahead of Print
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Zika virus (ZIKV) outbreaks occur sporadically in tropical and subtropical regions. At present, there are no licensed vaccines or specific treatments available for ZIKV. Ivermectin is approved for use in humans as an antiparasitic drug. In this study, we conducted in vitro cell culture and in vivo experiments in rhesus macaque hosts and Aedes aegypti vectors to investigate the potential of ivermectin as an inhibitor of ZIKV infection. In LLC-MK2 mammalian cells, ivermectin inhibited ZIKV growth in vitro with 50% inhibitory concentration (IC50) values in the ranges of 7.4–21.3 µM and 4.0–11.6 µM for African and Asian genotypes, respectively. In C6/36 mosquito cells, ivermectin inhibited ZIKV growth in vitro with IC50 values in the ranges of 10.1–17.4 µM and 8.0–15.6 µM for the African and Asian genotypes, respectively. Despite these in vitro results, high-dose ivermectin prophylaxis (1.2 mg/kg for 3 consecutive days) failed to prevent ZIKV infection in rhesus macaque and did not alter ZIKV IgM antibody production. The secondary transfer of ivermectin from nonhuman primate blood to mosquito vectors at 3 days post-ZIKV inoculation and after the last dose of ivermectin administration showed no reduction in ZIKV replication in mosquitoes. However, mosquito survival rates were significantly (P <0.0001) lower after exposure to ivermectin, thereby potentially impacting ZIKV transmission through increased vector mortality. However, further investigation is needed to determine dosing regimens that may realize these effects in vivo.

Author Notes

Financial support: This work was funded by the Military Infectious Disease Research Program (MIDRP, MI220083). The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. All authors declare to have no commercial or financial conflict of interest.

Disclosures: This material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting true views of the Department of the Army or the Department of Defense. Research was conducted under an approved animal use protocol in an Association for Assessment and Accreditation for Laboratory Animal Care International (AAALACi)-accredited facility in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals, and it adheres to the principles stated in Guide for the Care and Use of Laboratory Animals, NRC Publication, 2011 edition. The U.S. Army Medical Directorate-Armed Forces Research Institute of Medical Sciences (USAMD-AFRIMS) Institutional Animal Care and Use Committee and the Animal Use Review Division, U.S. Army Medical Research and Materiel Command reviewed and approved this ivermectin and chloroquine interaction in macaques antimicrobial agents and chemotherapy study (PN16-03). This protocol was executed in compliance with Thai laws; Guide for the Care and Use of Laboratory Animals, 8th edition; the Animals for Scientific Purposes; the Animal Welfare Act; and all applicable U.S. Department of Agriculture, Office of Laboratory Animal Welfare and U.S. Department of Defense guidelines. The Institutional Animal Care and Use Committee (IACUC) protocol number is PN20-02. The USAMD-AFRIMS animal care and use program is fully accredited by the AAALACi. Animals enrolled in this study were part of an environmental enrichment program, which aims to enhance animal well-being by providing the macaques with sensory and motor stimulation for facilitating the expression of species-typical behaviors and promoting psychological well-being. All macaques were housed under conditions that provide sufficient space in accordance with established rules and regulations. Macaques were housed individually; however, opportunities for direct and indirect contact with conspecifics were provided to maintain their social environment. Animal care and husbandry were provided throughout the study by trained personnel and under the direction of licensed veterinarians.

Current contact information: Thomas S. Cotrone, Joint Pathology Center, Silver Spring, MD, E-mail: thomas.s.cotrone.mil@health.mil. Kevin Kobylinski, Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand, E-mail: kobylinskikevin@gmail.com. Alongkot Ponlawat, Department of Entomology, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand, E-mail: alongkotp.fsn@afrime.org. Rawiwan Im-Erbsin and Piyanate Sunyakumthorn, Department of Veterinary Medicine, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand, E-mails: rawiwani.fsn@afrims.org and piyanates.fsn@afrims.org. Pattaraporn Vanachayangkul, Department of Bacterial and Parasitic Diseases, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand, E-mail: pattarapornv.fsn@afrims.org. Yongyuth Poolpanichupatam, Jindarat Lohachanakul, Chonticha Klungthong, and Taweewun Hunsawong, Department of Virology, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand, E-mails: yongyuthp.fsn@afrims.org, jindaratl.ca@afrims.org, chontichak.fsn@afrims.org, and taweewunh.fsn@afrims.org. Aaron Farmer, Viral Disease Program, Walter Reed Army Institute of Research, Silver Spring, MD, E-mail: aaron.r.farmer.mil@health.mil. Stefan Fernandez, 512th Field Hospital, Kaiserslautern, Germany, E-mail: stefan.fernandez.mil@army.mil.

Address correspondence to Taweewun Hunsawong, Department of Virology, Walter Reed Army Institute of Research-Armed Forces Research Institute of Medical Science (WRAIR-AFRIMS), Ratchathewi Rd., Ratchawithi, Bangkok 10400, Thailand. E-mail: taweewunh.fsn@afrims.org
Copyright:
© The author(s) 2024
Received:
19 Mar 2024
|
Accepted:
26 Sep 2024
|
Published Online:
17 Dec 2024
Cover The American Journal of Tropical Medicine and Hygiene
The American Journal of Tropical Medicine and Hygiene
Print ISSN:
0002-9637
Online ISSN:
1476-1645
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