Enhanced Inhibition of Human Immunodeficiency Virus Type 1 by Met-Stromal-Derived Factor 1β Correlates with Down-Modulation of CXCR4
| Autor: | Zhijian Lu, Steven H. Herrmann, Stephen L. Swanberg, John M. Mccoy, Michelle Dziejman, Bruce D. Walker, Andrew D. Luster, Otto O. Yang |
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| Rok vydání: | 1999 |
| Předmět: |
Receptors
CXCR4 Anti-HIV Agents Chemokine receptor CCR5 Molecular Sequence Data Immunology Down-Regulation Microbiology Chemokine receptor Methionine Viral entry Virology Humans Amino Acid Sequence CXCL16 biology virus diseases Chemokine CXCL12 Virus-Cell Interactions Cell biology CXCL2 Biochemistry Insect Science HIV-1 biology.protein XCL2 CXCL9 Calcium Chemokines CXC CCL21 |
| Zdroj: | Journal of Virology. 73:4582-4589 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.73.6.4582-4589.1999 |
| Popis: | CXCR4 (CXC chemokine receptor 4; also called fusin or LESTR) was the first chemokine receptor identified as a necessary coreceptor for human immunodeficiency virus type 1 (HIV-1) cell entry (15). T-cell line-tropic (T-tropic) strains of HIV-1 were found to require CXCR4 in addition to CD4 to bind and enter target cells. The observations that monocyte-tropic (M-tropic) virus strain entry could be blocked by the chemokines macrophage inflammatory protein (MIP)-1α, MIP-1β, and RANTES (regulated an activation normal T cell expressed and secreted) (8) rapidly led to the identification of CCR5 (CC chemokine receptor 5) as another important coreceptor (1, 10, 14, 37). The ability of these CCR5 ligands to block M-tropic HIV-1 prompted a search for analogous CXCR4 ligands that can block T-tropic HIV-1. Stromal-cell-derived factor 1α and 1β (SDF-1α and -1β), which are splice variants of the same gene (31, 43, 47) differing by four additional amino acids at the C terminus of SDF-1β, were found to bind and signal through CXCR4 and block T-tropic virus entry (5, 32). The precise mechanism(s) by which SDF-1 interferes with T-tropic HIV-1 cell entry is not known. Recent work has examined the biological activity of SDF-1, including chemotaxis, receptor binding, calcium mobilization, and down-modulation of CXCR4 (2, 9, 17, 18, 44). Several reports have shown that small molecules can block T-tropic strains in vitro (12, 19, 30, 40). Inhibition by SDF-1 or small molecules is thought to involve competitive binding to CXCR4, blocking binding of viral gp120 (12); the role of downstream events, such as receptor down-modulation or postreceptor signaling, remains to be fully elucidated. Two groups have reported that C-terminal-truncated CXCR4 supports T-tropic HIV-1 entry but is not down-modulated following exposure to SDF-1; without chemokine-mediated receptor down-modulation, SDF-1 does not efficiently block viral replication as measured by HIV-1 p24 protein production (2, 44). These results imply that down-modulation of CXCR4 or postreceptor signaling plays a crucial role in the antiviral activity of SDF-1. In the present study we examine the activities of two forms of SDF-1: SDF-1β, beginning with the amino-terminal amino acid lysine, which is believed to represent the native amino-terminal sequence (6), and Met-SDF-1β, which has an added N-terminal methionine. We find significant functional differences between these two molecules. Our results indicate that receptor down-modulation is a crucial component in the inhibition of HIV-1 infection by SDF-1β. |
| Databáze: | OpenAIRE |
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