Two components of the HIV-1 envelope protein, gp120 and gp41, were found to potently inhibit the expression and function of chemoattractant receptors on human monocytes, including the receptors for chemokines as well as for bacterial chemotactic peptide fMLF. The inhibitory effects of HIV-1 envelope proteins was not due to a direct competition for the receptors with other chemoattractants, but rather, through a """"""""heterologous desensitization"""""""" mechanism involving the activation of protein kinase C. Gp120 also inhibited the expression and function of chemokine receptor CXCR4 in human CD4+ T lymphocytes, and this required signaling events mediated by tyrosine kinase(p56lck) activation. We further investigated the interaction of human leukocytes with peptide domains in HIV-1 envelope proteins that are important in HIV-1 fusion and found that two 7 transmembrane receptors on human phagocytes, FPR and FPRL1, are activated by some HIV-1 envelope domains. These receptors were originally identified as activation sites for chemotactic N-formylated peptides, either synthetic or produced by certain bacteria and cytoplasmic mitochondria. These observations suggest that while HIV-1 envelope proteins are crucial in mediating viral invasion, their domains may also elicit host immune responses possibly resulting in activation of host innate immune responses. However, a potent and prolonged activation of immune cells may alsoculminate in unresponsiveness of the cells to other stimulants, a consequence of """"""""desensitization"""""""" which could be beneficial for AIDS-related opportunistic infection. Since the chemokine receptors CCR5 and CXCR4 are crucial co-receptors of HIV-1 infection of human cells, we investigated the possibility to utilize receptor desensitization as a means of develop novel anti-HIV-1 agents. We have revealed that activation of FPR by the bacterial fMLF was followed by a rapid serine phosphorylation of CCR5 mediated by protein kinase C, in association with the attenuation of CCR5 including its capacity to act as an HIV-1 coreceptor. We also identified a random synthetic peptide, W peptide, that activates both FPR and FPRL1 and inhibits HIV-1 infection of receptor transfected cell lines as well as human peripheral blood mononuclear cells. W peptide contains a D-amino acid in its sequence and thus may be resistant to enzymatic degradation and more suitable for in vivo administration to test its anti-HIV-1 efficacy. Serum amyloid A (SAA), an acute phase protein, is normally present in serum at 0.1 mM levels, but increases by 1000 fold in systemic inflammatory conditions. Chronic inflammatory conditions with elevated serum SAA may culminate in amyloidosis, characterized by deposition of """"""""amyloid"""""""" fibrils in tissues and associated with progressive destruction of organ function. We found that recombinant human (rh) SAA exhibited considerable chemoattractant activity for human leukocytes in vitro and induced infiltration of these cells at injection sites in mice, suggesting that SAA, when present locally, may play a proinflammatory role. In an effort to identify the cell receptor for SAA, we carefully evaluated the pattern of cell signaling induced by SAA and cross-desensitization by other chemotactic factors. We found that the bacterial derived chemotactic peptide fMLP at high concentrations was able to inhibit the cell response to subsequent stimulation with SAA, suggesting that SAA might use a leukocyte receptor for which fMLP has low affinity. By using cell lines engineered to express genes encoding various seven-transmembrane, G-protein coupled receptors, we identified a receptor termed FPRL1 to be specifically bound and activated by SAA. The identification of the receptor used by SAA will greatly facilitate the further research on the role of SAA in acute phase responses and tissue amyloidosis.
Showing the most recent 10 out of 35 publications
