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.
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.
Lane
B R
BR
Department of Internal Medicine, Graduate Program in Cellular and Molecular Biology, School of Public Health, University of Michigan Medical Center, Ann Arbor 48109, USA.
Markovitz
D M
DM
Woodford
N L
NL
Rochford
R
R
Strieter
R M
RM
Coffey
M J
MJ
D000276:Adjuvants, Immunologic / Q000502:physiology; D000998:Antiviral Agents / Q000502:physiology*; D065100:CCR5 Receptor Antagonists; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000276:immunology; D019742:Chemokines, CC / Q000096:biosynthesis; D015536:Down-Regulation / Q000276:immunology; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D019713:Receptors, CCR5 / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D014779:Virus Replication / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000998:Antiviral Agents; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D019742:Chemokines, CC; D007166:Immunosuppressive Agents; D019713:Receptors, CCR5; D014409:Tumor Necrosis Factor-alpha