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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

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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.

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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

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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.

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The authors have no conflicts of interest to declare.

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Correspondence to Tadashi Nakasone or Naoki Yamamoto.

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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

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  • DOI: https://doi.org/10.1007/s00430-012-0254-1

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