Interference with the signaling capacity of CC chemokine receptor 5 can compromise its role as an HIV-1 entry coreceptor in primary T lymphocytes.
Interference with the signaling capacity of CC chemokine receptor 5 can compromise its role as an HIV-1 entry coreceptor in primary T lymphocytes.
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DOI：
10.1084/jem.190.5.591
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发表时间：
1999-09-06
期刊：
影响因子：
--
通讯作者：
Oppenheim JJ
中科院分区：
文献类型：
--
作者：
Wang JM;Oppenheim JJ
In this issue of The Journal of Experimental Medicine (1), Alfano et al. report the surprising results that pertussis toxin (PTX) as well as its cellular binding subunit, the B-oligomer, each blocked entry of monotropic (R5) strains of HIV-1 in primary T lymphocytes. Treatment of primary T cells with B-oligomer, unlike treatment of T cell lines, blocked calcium mobilization in response to the CCR5 chemokine ligand macrophage inflammatory protein-1ß (MIP-1ß), but had no effect on cell surface expression of CCR5 and binding of MIP-1ß or HIV-1 envelope gp120. Alfano et al. further demonstrate that B-oligomer blocks cocapping of CCR5 and CD4 induced by R5 HIV-1, but does not affect cocapping of CXCR4 and CD4 after incubation with T tropic (X4) virus. They documented that the B-oligomer signals by itself and induces calcium mobilization in primary T lymphocytes. Based on these activating effects, the authors hypothesize that the inhibitory effect of B-oligomer is probably a consequence of cross-desensitization of CCR5, although the cellular receptor for B-oligomer has not yet been defined. These findings argue for the requirement of an intact signaling capacity for CCR5 to act as an HIV-1 fusion coreceptor in primary T cells and suggest a novel approach to the design of therapeutic inhibitors of CCR5. There are a number of research reports that provide added insights concerning the mechanistic basis for these provocative findings.The current model of the HIV-1 fusion predicts that after binding of the envelope gp120 to the CD4 molecule, a conformational change in gp120 ensues, which enables its critical domain (or domains) to engage one of the chemokine receptors. This process is necessary for the fusogenic conversion of HIV-1 gp41 and the exposure of its fusion peptide domain (2, 3). The usage of chemokine receptors by HIV-1 Env and the ability of receptor-specific chemokine ligands to prevent HIV-1 fusion and infection raised the question whether the process of HIV-1 fusion is passive or requires chemokine receptor signals. A number of studies of CCR5 have suggested that chemokine receptor signaling may be dispensable for its role as an HIV-1 fusion coreceptor (4–6). For example, PTX did not interfere with the capacity of HIV-1 to infect T cell lines in vitro. Furthermore, truncation of the COOH tail of CCR5 or mutation of the highly conserved aspartate-arginine-tyrosine (DRY) sequence in the second cytoplasmic loop each ef-
