PMC:1082716 / 13402-16218 JSONTXT

{"project":"2_test","denotations":[{"id":"15807900-12663038-134044040","span":{"begin":686,"end":688},"obj":"12663038"},{"id":"15807900-10079202-134044041","span":{"begin":998,"end":1000},"obj":"10079202"},{"id":"15807900-11022134-134044042","span":{"begin":1014,"end":1016},"obj":"11022134"},{"id":"15807900-11784140-134044043","span":{"begin":2399,"end":2401},"obj":"11784140"},{"id":"15807900-15689171-134044044","span":{"begin":2402,"end":2404},"obj":"15689171"},{"id":"15807900-15689171-134044045","span":{"begin":2686,"end":2688},"obj":"15689171"}],"text":"Discussion\nTaken together our results suggest that, at least under some conditions, the generation of intracellular signals by the chemokine co-receptor during HIV infection might be necessary for productive infection. Since Peptide 3 powerfully inhibited CCR5-dependent HIV infection of THP-1 cells under conditions where gp120 binding to CCR5 was unaffected but chemotaixs in response to RANTES was profoundly blocked, it is likely that at least some of the signals elicted by CCR5 occupation that result in chemotaxis are required for successful infection of the cell by HIV. Since BSCIs, such as Peptide 3, do not block chemokine receptor internalisation induced by ligand binding [27], it seems likely that the HIV successfully entered the cell in the presence of Peptide 3, but that some later stage in the viral life cycle was dependent on one or more intracellular signal generated by chemokine receptor occupancy. These results are consistent with, but extend, the findings of Guntermann [24] and Montes [25] who saw similar effects with pertussis toxin and a MEK inhibitor.\nIt is unclear why Peptide 3 blocked CCR5-dependent HIV infection of THP-1 cells but had no effect on CXCR4-dependent infection of Jurkat T-cells under similar condtions (even though Peptide 3 efficiently blocks SDF1α dependent chemotaxis). It is possible that infection of certain cell types (such as monocyte/macrophage cells) is more dependent on a chemokine receptor-induced intracellular signal than infection of other cell types (such as T-lymphocytes). This may reflect the fact the the Jurkat cells were proliferating at the time of infection, whereas the THP-1 derived macrophages were quiescent. However, it is also possible that this difference is due to the particularly high levels of CXCR4 which are expressed on Jurkat T cells. The high levels of receptor on this cell line might render infection relatively insensitive to intracellular signalling requirements compared with native T-cells or other cell types expressing physiological levels of chemokine co-receptors.\nIrrespective of the reasons for this difference, our preliminary studies illustrate the need to further investigate the role of intracellular signals induced by co-receptor occupancy as participants in the viral life cycle. Furthermore, the recent discovery of much more potent non-peptide BSCIs, such as the acylaminocaprolactams [34,35], opens up the possibility that interfering with chemokine receptor-induced signalling might offer an alternative therapeutic strategy to blocking chemokine receptor binding. The best acylaminocaprolactam BSCIs are cheap, orally bioavailable and apparently free of acute toxicity [35], and, on the basis of studies such as ours, warrant further investigation as part of an antiviral combination therapy for HIV."}