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HIV envelope proteins differentially utilize CXCR4 and CCR5 coreceptors for induction of apoptosis
1Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. qyao@bimcore.emory.edu
Abstract:
The involvement of CXCR4 and CCR5 coreceptors in apoptosis induced by the HIV envelope (Env) proteins has not been well defined. We found that simian human immunodeficiency virus (SHIV) virus-like particles (VLPs) containing HIV Env proteins preferentially induce apoptosis of cells corresponding to their coreceptor usage in a CD4+ T cell line. We also demonstrated that induction of apoptosis by SHIV VLPs is correlated with coreceptor usage in a non-T cell line. We examined the effects of SHIV VLPs containing Env proteins derived from either a T-cell-tropic HIV (BH10) strain or a dual-tropic HIV (89.6) strain on induction of apoptosis in recombinant CD4+ human osteosarcoma (HOS) cells expressing either CXCR4 (HOS-CD4.CXCR4) or CCR5 coreceptors (HOS-CD4.CCR5). HOS-CD4.CXCR4 or HOS-CD4.CCR5 cells were activated with concanavalin A and cocultured with VLPs. By TUNEL (TdT-mediated dUTP-X nick end labeling) fluorescence staining and flow cytometry assays, SHIV BH10 VLPs were found to preferentially induce apoptosis in HOS-CD4.CXCR4 cells but not in HOS-CD4 or HOS-CD4.CCR5 cells. On the other hand, SHIV 89.6 VLPs induced an elevated level of apoptosis in both HOS-CD4.CXCR4 and HOS-CD4.CCR5 cells in a dose-dependent fashion. These data demonstrate that T-cell-tropic BH10 Env preferentially utilizes CXCR4, but not CCR5, for induction of apoptosis, whereas dual-tropic 89.6 Env induces apoptosis in both CXCR4- and CCR5-containing cell lines.
Insights
Simian human immunodeficiency virus (SHIV) envelope proteins induce apoptosis by utilizing specific coreceptors. T-cell-tropic strains use CXCR4, while dual-tropic strains use both CXCR4 and CCR5.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- The role of CXCR4 and CCR5 coreceptors in HIV envelope (Env)-induced apoptosis remains unclear.
- HIV Env proteins mediate viral entry and can trigger programmed cell death.
Purpose of the Study:
- To investigate the differential involvement of CXCR4 and CCR5 coreceptors in apoptosis induced by HIV Env proteins.
- To determine coreceptor usage for apoptosis induction by T-cell-tropic and dual-tropic HIV strains.
Main Methods:
- Simian human immunodeficiency virus (SHIV) virus-like particles (VLPs) with HIV Env proteins were used.
- Apoptosis was assessed in recombinant human osteosarcoma (HOS) cells expressing CXCR4 or CCR5.
- TUNEL staining and flow cytometry quantified apoptosis levels.
Main Results:
- SHIV VLPs with T-cell-tropic BH10 Env preferentially induced apoptosis in CXCR4-expressing cells.
- SHIV VLPs with dual-tropic 89.6 Env induced apoptosis in both CXCR4- and CCR5-expressing cells.
- Apoptosis induction correlated with coreceptor usage in both T cell and non-T cell lines.
Conclusions:
- T-cell-tropic HIV Env proteins utilize CXCR4 for apoptosis induction.
- Dual-tropic HIV Env proteins can utilize both CXCR4 and CCR5 to induce apoptosis.
- Coreceptor tropism dictates the induction of apoptosis by HIV Env proteins.