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PMID:10490959

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Citation

Lane, BR, Markovitz, DM, Woodford, NL, Rochford, R, Strieter, RM and Coffey, MJ (1999) TNF-alpha inhibits HIV-1 replication in peripheral blood monocytes and alveolar macrophages by inducing the production of RANTES and decreasing C-C chemokine receptor 5 (CCR5) expression. J. Immunol. 163:3653-61

Abstract

The pathogenesis of HIV-1 infection is influenced by the immunoregulatory responses of the host. Macrophages present in the lymphoid tissue are susceptible to infection with HIV-1, but are relatively resistant to its cytopathic effects and serve as a reservoir for the virus during the course of disease. Previous investigators have demonstrated that increased serum levels of TNF-alpha contribute to the clinical symptoms of AIDS and that TNF-alpha stimulates the production of HIV-1 in chronically infected lymphocytic and monocytic cell lines by increasing HIV-1 gene expression. Although previous studies have suggested that TNF-alpha may increase HIV-1 infection of primary human mononuclear cells, some recent studies have indicated that TNF-alpha suppresses HIV-1 infection of macrophages. We now demonstrate that TNF-alpha suppresses HIV-1 replication in freshly infected peripheral blood monocytes (PBM) and alveolar macrophages (AM) in a dose-dependent manner. As TNF-alpha has been shown to increase the production of C-C chemokine receptor (CCR5)-binding chemokines under certain circumstances, we hypothesized that TNF-alpha inhibits HIV-1 replication by increasing the expression of these HIV-suppressive factors. We now show that TNF-alpha treatment of PBM and AM increases the production of the C-C chemokine, RANTES. Immunodepletion of RANTES alone or in combination with macrophage inflammatory protein-1alpha and -1beta block the ability of TNF-alpha to suppress viral replication in PBM and AM. In addition, we found that TNF-alpha treatment reduces CCR5 expression on PBM and AM. These findings suggest that TNF-alpha plays a significant role in inhibiting monocytotropic strains of HIV-1 by two distinct, but complementary, mechanisms.

Links

PubMed

Keywords

Adjuvants, Immunologic/physiology; Antiviral Agents/physiology; Cell Membrane/immunology; Cell Membrane/metabolism; Chemokine CCL5/biosynthesis; Chemokine CCL5/immunology; Chemokines, CC/biosynthesis; Down-Regulation/immunology; HIV-1/immunology; HIV-1/metabolism; Humans; Immunosuppressive Agents/antagonists & inhibitors; Immunosuppressive Agents/pharmacology; Macrophages, Alveolar/immunology; Macrophages, Alveolar/metabolism; Macrophages, Alveolar/virology; Monocytes/immunology; Monocytes/metabolism; Monocytes/virology; Receptors, CCR5/antagonists & inhibitors; Receptors, CCR5/biosynthesis; Tumor Necrosis Factor-alpha/antagonists & inhibitors; Tumor Necrosis Factor-alpha/physiology; Virus Replication/immunology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:CCL5

involved_in

GO:0045071: negative regulation of viral genome replication

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNFA

involved_in

GO:0045080: positive regulation of chemokine biosynthetic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNFA

involved_in

GO:0045071: negative regulation of viral genome replication

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNFA

involved_in

GO:0032722: positive regulation of chemokine production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNFA

involved_in

GO:0009615: response to virus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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