Role of chemokine receptors in HIV infection and progression.

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1. The role of CCR3 in HIV infection. C CR3, a receptor for chemokines such as eotaxin, has been recently identified as a coreceptor for certain types of HIV-1. Although CCR3 is strongly expressed on eosinophils in human peripheral blood cells, the expression on other cell types and its role in HIV infection have not been fully elucidated. In the current project, we have established monoclonal antibody against human CCR3. Using CCR3-expressing human glioma cells and CCR3-tropic HIV isolates, we found that this mAb specifically blocked HIV infection in vitro. Thus, this mAb provides a valuable probe in investigating the expression and function of HIV coreceptor, CCR3.2. Signal transduction pathways involving HIVenv-dependent cell fusion. Using HIVenv-dependent cell fusion system, we demonstrated that cytochalacin D and herbimycin but not pertussis toxin significantly inhibited HIV entry to cells. Moreover, confocal microscopy revealed colocalization of phosphotyrosyl proteins and F- act … More in in areas where cell membranes are about to fuse. These results suggest that protein tyrosine kin ase cascades and cytoskeletal reorganization play a critical role in HIVenv-dependent cell fusion. However, we found that HIVenv-dependent cell fusion could occur even in the absence of various non-receptor tyrosine kinases, including Src, Fyn, Lyn, FAK, or Abl, suggesting that these tyrosine kinases are not absolutely necessary for HIV-entry. However, redundancy commonly exists among these kinases. For example, we found that FAX-deficient cells expressed another FAK-family kinase, CAKbeta, which was considered to substitute the function of FAK.We also found that stimulation of human T cells with SDF1, a natural ligand for HTV coreceptor CXCR4, induced tyrosine phosphorylation of p105CasL.Since p105CasL is a signaling molecule involving in T cell receptor signal cascades, signals triggered by coreceptor engagement may play a role in abnormal function of T cells in HIV infected individuals. Less