Potent, broad-spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140

CCR5 serves as a requisite fusion coreceptor for clinically relevant strain s of human immunodeficiency virus type 1 (HIV-1) and provides a promising t arget for antiviral therapy. However, no study to date has examined whether monoclonal antibodies, small molecules, or other nonchemokine agents posse ss broad-spectrum activity against the major genetic subtypes of HIV-1. PRO 140 (PA14) is an anti-CCR5 monoclonal antibody that potently inhibits HIV- 1 entry at concentrations that do not affect CCR5's chemokine receptor acti vity. In this study, PRO 140 was tested against a panel of primary HTV-1 is olates selected for their genotypic and geographic diversity. In quantitati ve assays of viral infectivity, PRO 140 was compared with RANTES, a natural CCR5 ligand that can inhibit HIV-1 entry by receptor downregulation as wel l as receptor blockade. Despite their divergent mechanisms of action and bi nding epitopes on CCR5, low nanomolar concentrations of both PRO 140 and RA NTES inhibited infection of primary peripheral blood mononuclear cells (PBM C) by all CCR5-using (R5) viruses tested. This is consistent with there bei ng a highly restricted pattern of CCR5 usage by R5 viruses. In addition, a panel of 25 subtype C South African R5 viruses were broadly inhibited by PR O 140, RANTES, and TAK-779, although similar to 30-fold-higher concentratio ns of the last compound were required. Interestingly, significant inhibitio n of a dualtropic subtype C virus was also observed. Whereas PRO 140 potent ly inhibited HIV-1 replication in both PBMC and primary macrophages, RANTES exhibited limited antiviral activity in macrophage cultures. Thus CCR5-tar geting agents such as PRO 140 can demonstrate potent and genetic-subtype-in dependent anti-RIV-1 activity.