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. Since SAA is an amyloidogenic protein associated with chronic inflammation, we examined the possibility that other amyloidogenic proteins, such as Ab42, may use similar receptors for cell interaction. Ab42 is a 42 amino acid form of the b amyloid peptide and is a key causative factor of Alzheimer's disease (AD). In addition to its reported direct toxic effect on nerve cells, Ab42 has been found to activate mononuclear phagocytic cells in the brain which results in inflammation and release of neurotoxic mediators. We have demonstrated FPRL1 to be used by Ab42 to induce migration and activation of mononuclear phagocytes. In addition, we have detected a high level expression of the FPRL1 gene in CD11b positive phagocytic cells surrounding and infiltrating the lesions in the brain tissues of AD patients. These results suggest an active involvement of this receptor in the proinflammatory aspects of AD lesions. Interestingly, recent research by our group also revealed FPRL1 to be a receptor for a peptide fragment of the human prion protein, which, with its isoforms, causes """"""""Kuru"""""""" or """"""""Mad Cow Disease"""""""". The peptide fragment Prp10-126 forms aggregates and activates mononuclear phagocytes to release mediators toxic to neurons in vitro. Studies are being conducted to elucidate the role of FPRL1 in the pathogenesis of neurodegenerative diseases and its potential as a therapeutic target.
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