Specific interactions between the viral coreceptor CXCR4 and the biguanide-based compound NB325 mediate inhibition of human immunodeficiency virus type 1 infection.
The present studies were conducted to better define the mechanism of action of polyethylene hexamethylene biguanide (PEHMB) (designated herein as NB325), which was shown in previous studies to inhibit infection by the human immunodeficiency virus type 1 (HIV-1). Fluorescence-activated flow cytometric analyses of activated human CD4(+) T lymphocytes exposed to NB325 demonstrated concentration-dependent reductions in CXCR4 epitope recognition in the absence of altered recognition of selected CD4 or CD3 epitopes. NB325 also inhibited chemotaxis of CD4(+) T lymphocytes induced by the CXCR4 ligand CXCL12. However, NB325 did not cause CXCR4 internalization (unlike CXCL12) and did not interfere with CXCL12 binding. Additional flow cytometric analyses using antibodies with distinct specificities for extracellular domains of CXCR4 demonstrated that NB325 specifically interfered with antibody binding to extracellular loop 2 (ECL2). This interaction was confirmed using competitive binding analyses, in which a peptide derived from CXCR4 ECL2 competitively inhibited NB325-mediated reductions in CXCR4 epitope recognition. Collectively, these results demonstrate that the biguanide-based compound NB325 inhibits HIV-1 infection by specifically interacting with the HIV-1 coreceptor CXCR4.
Thakkar
Nina
N
Department of Microbiology and Immunology, Center for Molecular Therapeutics and Resistance, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19102, USA.
Pirrone
Vanessa
V
Passic
Shendra
S
Zhu
Wei
W
Kholodovych
Vladyslav
V
Welsh
William
W
Rando
Robert F
RF
Labib
Mohamed E
ME
Wigdahl
Brian
B
Krebs
Fred C
FC
D019380:Anti-HIV Agents / Q000494:pharmacology*; D001645:Biguanides / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D010455:Peptides / Q000737:chemistry; D054398:Receptors, CCR4 / Q000187:drug effects*
D019380:Anti-HIV Agents; D001645:Biguanides; D017252:CD3 Complex; D054377:Chemokine CXCL12; C539938:NB325; D010455:Peptides; D054398:Receptors, CCR4