Abstract
We evaluated the long-term effects of the single oral administration of a new CXCR4 antagonist, KRH-3955, on elevation of white blood cell (WBC), neutrophil and lymphocyte counts in normal cynomolgus monkeys. In the monkeys treated with 0, 2, 20, 200 mg/kg of the compound, WBC, neutrophil and lymphocyte counts increased dramatically at 2 days after treatment. This effect was dose-dependent, and these cell counts remained elevated 15 days after drug treatment. Since neutrophils are the most abundant WBCs in circulation and bone marrow neutrophil exhaustion impairs the response to bacterial infections, it is intriguing to exploit this pharmacological increase of neutrophils as a tool to address its influence on viral infections in vivo. The SHIV infection studies using the SHIV-KS661c/cynomolgus monkey model showed that a single oral administration of KRH-3955 (100 mg/kg) approximately 24 h before virus exposure did not prevent infection, although it did prevent CD4 cell depletion in 3/3 monkeys. Furthermore, single oral administration of the drug 2 weeks before viral exposure rescued CD4 cells in 1/3 monkeys. This prevention of CD4 cell depletion was observed in both blood and lymphoid tissues. These results show that natural course of the SHIV infection is modulated by artificial increase of neutrophils and lymphocytes caused by KRH-3955 in the cynomolgus monkey model.
Abbreviations
- CXCR4:
-
C-X-C motif receptor 4
- CCR5:
-
C–C motif receptor 5
- SDF-1:
-
Stromal-derived factor-1
- CBC:
-
Complete blood cell count
- PrEP:
-
Pre-exposure prophylaxis
- SHIV:
-
Simian human immunodeficiency virus
- PBL:
-
Peripheral blood lymphocytes
- PB:
-
Peripheral blood
- LT:
-
Lymphoid tissue
- LN:
-
Lymph node
- WBC:
-
White blood cell
- AZT:
-
Zidovudine
- IC50:
-
Half maximal inhibitory concentration
References
Bouma G, Ancliff PJ, Thrasher AJ, Burns SO (2010) Recent advances in the understanding of genetic defects of neutrophil number and function. Br J Haematol 151:312–326
Navarini AA, Lang KS, Verschoor A et al (2009) Innate immune-induced depletion of bone marrow neutrophils aggravates systemic bacterial infections. Proc Natl Acad Sci USA 106:7107–7112
Raffaghello L, Bianchi G, Bertolotto M et al (2008) Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche. Stem Cells 26:151–162
Babior B (2001) Production, distribution and fate of neutrophils. McGraw-Hill, New York, pp 753–759
Nauseef WM (2007) How human neutrophils kill and degrade microbes: an integrated view. Immunol Rev 219:88–102
Rogers HW, Unanue ER (1993) Neutrophils are involved in acute, nonspecific resistance to Listeria monocytogenes in mice. Infect Immun 61:5090–5096
Rakhmilevich AL (1995) Neutrophils are essential for resolution of primary and secondary infection with Listeria monocytogenes. J Leukoc Biol 57:827–831
Lundqvist-Gustafsson H, Bengtsson T (1999) Activation of the granule pool of the NADPH oxidase accelerates apoptosis in human neutrophils. J Leukoc Biol 65:196–204
Peled A, Wald O, Burger J (2012) Development of novel CXCR4-based therapeutics. Expert Opin Investig Drugs 21:341–353
Hendrix CW, Flexner C, MacFarland RT et al (2000) Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers. Antimicrob Agents Chemother 44:1667–1673
Ichiyama K, Yokoyama-Kumakura S et al (2003) A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity. Proc Natl Acad Sci USA 100:4185–4190
Murakami T, Kumakura S, Yamazaki T et al (2009) The novel CXCR4 antagonist KRH-3955 is an orally bioavailable and extremely potent inhibitor of human immunodeficiency virus type 1 infection: comparative studies with AMD3100. Antimicrob Agents Chemother 53:2940–2948
Murakami T, Yamamoto N (2010) Role of CXCR4 in HIV infection and its potential as a therapeutic target. Future Microbiol 5:1025–1039
Shinohara K, Sakai K, Ando S et al (1999) A highly pathogenic simian/human immunodeficiency virus with genetic changes in cynomolgus monkey. J Gen Virol 80:1231–1240
Kaizu M, Ami Y, Nakasone T et al (2003) Higher levels of IL-18 circulate during primary infection of monkeys with a pathogenic SHIV than with a nonpathogenic SHIV. Virology 313:8–12
Nakasone T, Sakai K, Ami Y et al (2002) Genetic and biological characterization of a highly pathogenic molecular clone, SHIV-C2/1 KS661. J Med Primatol 31:277
Nakasone T, Kanekiyo M, Yoshino N et al (2007) Cell-associated SHIV infection in cynomolgus monkeys. J Med Primatol 36:308–309
Ami Y, Izumi Y, Matsuo K et al (2005) Priming-boosting vaccination with recombinant Mycobacterium bovis bacillus Calmette-Guérin and a nonreplicating vaccinia virus recombinant leads to long-lasting and effective immunity. J Virol 79:12871–12879
Murakami T, Eda Y, Nakasone T et al (2009) Postinfection passive transfer of KD-247 protects against simian/human immunodeficiency virus-induced CD4+ T-cell loss in macaque lymphoid tissue. AIDS 23:1485–1494
Someya K, Xin KQ, Ami Y et al (2007) Chimeric adenovirus type 5/35 vector encoding SIV gag and HIV env genes affords protective immunity against the simian/human immunodeficiency virus in monkeys. Virology 367:390–397
Motohara M, Ibuki K, Miyake A et al (2006) Impaired T-cell differentiation in the thymus at the early stages of acute pathogenic chimeric simian-human immunodeficiency virus (SHIV) infection in contrast to less pathogenic SHIV infection. Microbes Infect 8:1539–1549
Miyake A, Ibuki K, Enose Y et al (2006) Rapid dissemination of a pathogenic simian/human immunodeficiency virus to systemic organs and active replication in lymphoid tissues following intrarectal infection. J Gen Virol 87:1311–1320
Matsuda K, Inaba K, Fukazawa Y et al (2010) In vivo analysis of a new R5 tropic SHIV generated from the highly pathogenic SHIV-KS661, a derivative of SHIV-89.6. Virology 399:134–143
Lu Y, Salvato MS, Pauza CD et al (1996) Utility of SHIV for testing HIV-1 vaccine candidates in macaques. J Acquir Immune Defic Syndr Hum Retrovirol 12:99–106
Nakasone T, Murakami T, Yamamoto N (2012) Double oral administration of emtricitabine/tenofovir prior to virus exposure protects against highly pathogenic SHIV infection in macaques. Jpn J Infect Dis 65(4)
De Clercq E (2010) Recent advances on the use of the CXCR4 antagonist plerixafor (AMD3100, Mozobil™) and potential of other CXCR4 antagonists as stem cell mobilizers. Pharmacol Ther 128:509–518
Chow KY, Brotin É, Ben Khalifa Y et al (2010) A pivotal role for CXCL12 signaling in HPV-mediated transformation of keratinocytes: clues to understanding HPV-pathogenesis in WHIM syndrome. Cell Host Microbe 8:523–533
Acknowledgments
We would like to thank Dr. Heneine W, CDC, Atlanta, USA, and Dr. Tanaka Y, University of the Ryukyus, Okinawa, Japan, for helpful discussion. We are also grateful to Drs. Ono F and Katagai Y for performing the necropsy of monkeys, and Drs. Hiyaoka A and Komatsuzaki K, the Corporation for Production and Research of Laboratory Primates, Tsukuba, Japan, for animal care and sampling. This work was supported by grants from the Japanese Ministries of Education, Culture, Sports, Science and Technology (20390136, 13226027, 14406009 and 1941075), Health, Labour and Welfare (H18-005), and Human Health Science (H19-001) to NY, and Health, Labour and Welfare (H19-001) to TM.
Conflict of interest
The authors have no conflicts of interest to declare.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Nakasone, T., Kumakura, S., Yamamoto, M. et al. Single oral administration of the novel CXCR4 antagonist, KRH-3955, induces an efficient and long-lasting increase of white blood cell count in normal macaques, and prevents CD4 depletion in SHIV-infected macaques: a preliminary study. Med Microbiol Immunol 202, 175–182 (2013). https://doi.org/10.1007/s00430-012-0254-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00430-012-0254-1