Persistent interactions between biguanide-based compound NB325 and CXCR4 result in prolonged inhibition of human immunodeficiency virus type 1 infection.
We previously demonstrated that the biguanide-based compound NB325 inhibits human immunodeficiency virus type 1 (HIV-1) infection by interacting with the CXCR4 viral coreceptor. This interaction also appeared to be persistent, since HIV-1 infection was inhibited even when the virus was introduced subsequent to the removal of NB325 from the cell culture medium. The present studies were conducted to determine the extent and mechanism of this prolonged antiviral activity. Persistent inhibition of HIV-1 infection by NB325 was concentration dependent and was apparent up to 8 h after removal of the compound. Flow cytometric analyses of stimulated CD4(+) T lymphocytes exposed to NB325 demonstrated concentration-dependent reductions in CXCR4 extracellular loop 2 epitope recognition that were maintained up to 24 h after removal of the compound. CXCL12-induced chemotaxis was also persistently inhibited following pre-exposure to NB325. These results demonstrate that persistent inhibition of X4 HIV-1 infection by NB325 involves extended perturbation of the viral coreceptor CXCR4.
Thakkar
Nina
N
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
Pirrone
Vanessa
V
Passic
Shendra
S
Keogan
Shawn
S
Zhu
Wei
W
Kholodovych
Vladyslav
V
Welsh
William
W
Rando
Robert
R
Labib
Mohamed
M
Wigdahl
Brian
B
Krebs
Fred C
FC
D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001645:Biguanides / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D000939:Epitopes / Q000187:drug effects; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D019718:Receptors, CXCR4 / Q000378:metabolism*
D000998:Antiviral Agents; D001645:Biguanides; C527276:CXCR4 protein, human; D000939:Epitopes; C539938:NB325; D019718:Receptors, CXCR4