Medical Microbiology and Immunology

, Volume 202, Issue 2, pp 175–182

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

Rapid Communication

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.

Keywords

CXCR4 antagonist WBC mobilization SHIV HIV 

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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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.AIDS Research CenterNational Institute of Infectious DiseasesTokyoJapan
  2. 2.Kureha CorporationTokyoJapan
  3. 3.Faculty of Pharmaceutical SciencesSuzuka University of Medical SciencesMieJapan
  4. 4.Department of MicrobiologyNational University of SingaporeSingaporeSingapore

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