Blockade of X4-tropic HIV-1 cellular entry by GSK812397, a potent noncompetitive CXCR4 receptor antagonist.

GSK812397 is a potent entry inhibitor of X4-tropic strains of HIV-1, as demonstrated in multiple in vitro cellular assays (e.g., in peripheral blood mononuclear cells [PBMCs] and a viral human osteosarcoma [HOS] assay, mean 50% inhibitory concentrations [IC50s]+/-standard errors of the means were 4.

GSK983: a novel compound with broad-spectrum antiviral activity.

GSK983, a novel tetrahydrocarbazole, inhibits the replication of a variety of unrelated viruses in vitro with EC(50) values of 5-20 nM. Both replication of the adenovirus Ad-5 and the polyoma virus SV-40, and episomal maintenance of human papillomaviruses (HPV) and Epstein-Barr virus (EBV) are susceptible to GSK983. The compound does not inhibit all viruses; herpes simplex virus (HSV-1), human immunodeficiency virus (HIV), and lytic replication of EBV were not susceptible at concentrations below 1 microM.

Development of a novel high-throughput surrogate assay to measure HIV envelope/CCR5/CD4-mediated viral/cell fusion using BacMam baculovirus technology.

The initial event by which M-tropic HIV strains gain access to cells is via interaction of the viral envelope protein gp120 with the host cell CCR5 coreceptor and CD4. Inhibition of this event reduces viral fusion and entry into cells in vitro. The authors have employed BacMam baculovirus-mediated gene transduction to develop a cell/cell fusion assay that mimics the HIV viral/cell fusion process and allows high-throughput quantification of this fusion event.

Development of a high-throughput viral-free assay for the measurement of CCR5-mediated HIV/cell fusion.

M-tropic HIV strains gain access to their host cell via interaction of the viral envelope protein gp120 with the CCR5 coreceptor and CD4 located on the host cell. Inhibition of this event has been shown to reduce viral fusion and entry into cells in vitro. In the present study we describe the development of a novel cell/cell fusion assay that both mimics the viral/cell fusion process and allows quantification of this event.

CCR5 chemokine receptors: gatekeepers of HIV-1 infection.

With the discovery that CCR5 is the critical protein required for infection by M-tropic HIV, has come huge research efforts, both in academia and industry, to try to exploit this finding. Thus, research advances in the fields of virology, structural protein chemistry, and receptor pharmacology have combined to add a new understanding to the process of HIV fusion and possible mechanisms to prevent HIV entry. This review will approach this field from a receptor pharmacology viewpoint and outline some concepts of receptor allosterism and protein-protein interaction which may be relevant to CCR5 blockade.