TNF-α 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

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-α contribute to the clinical symptoms of AIDS and that TNF-α 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-α may increase HIV-1 infection of primary human mononuclear cells, some recent studies have indicated that TNF-α suppresses HIV-1 infection of macrophages. We now demonstrate that TNF-α suppresses HIV-1 replication in freshly infected peripheral blood monocytes (PBM) and alveolar macrophages (AM) in a dose-dependent manner. As TNF-α has been shown to increase the production of C-C chemokine receptor (CCR5)-binding chemokines under certain circumstances, we hypothesized that TNF-α inhibits HIV-1 replication by increasing the expression of these HIV-suppressive factors. We now show that TNF-α 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-1α and -1β block the ability of TNF-α to suppress viral replication in PBM and AM. In addition, we found that TNF-α treatment reduces CCR5 expression on PBM and AM. These findings suggest that TNF-α plays a significant role in inhibiting monocytotropic strains of HIV-1 by two distinct, but complementary, mechanisms.

Unique Profile of Proinflammatory Cytokines in Plasma of Drug-Naïve Individuals with Advanced HIV/TB Co-Infection

“…TNF-α has a primordial function in protection against Mtb infection [ 12 , 40 , 43 , 44 , 45 , 46 , 47 ]. In HIV-1 infection, TNF-α mediates the apoptosis of HIV-infected cells [ 48 ] and suppresses HIV-1 replication in the freshly infected peripheral blood monocytes [ 49 ]. Here, corroborating other studies [ 20 , 50 , 51 , 52 , 53 ], we found the plasma levels of TNF-α to be comparable in patients with HIV-1 and with TB monoinfections, but significantly decreased in patients with HIV-1/TB coinfection, although they did not reach significance in distinguishing coinfection from monoinfections ( p = 0.06), as plasma levels of IFN-γ did.…”

M1/M2 macrophages and their overlaps – myth or reality?

“…Antiviral cytokines released by M1 macrophages include TNFα, IL-1, IL-6, IL-8 and IL-12, which exert antiviral activities both directly and indirectly. For example, TNFα inhibits replication of viruses such as herpes simplex, swine fever virus and influenza [ 89 ], HIV-1, [ 90 ] and hepatitis B [ 91 ], which are also capable of enhancing the cytotoxicity of other leukocytes, such as NK cells, in an IL-β, IFN-β or IL-15-dependent fashion [ 92 ].…”

Immune responses to Tilapia lake virus infection: what we know and what we don’t know

“…It is therefore possible that such a significant upregulation in tnfa and in genes involved in the regulation of necroptosis during TILVD progression both drive the development of programmed necrosis as observed in multiple organs, especially in the liver of TiLV-infected fish. It might thus be a host-induced strategy to both inhibit viral replication as previously reported (72)(73)(74) and enhance inflammatory reactions to lessen viral reproduction. It will therefore be crucial to elucidate the contribution of necroptosis in TiLVD pathogenesis.…”

“…It induces endothelial adhesion molecules, which trigger the migration of innate immune cells, such as blood-borne dendritic cells (DCs), natural killer (NK) cells and macrophages, to the site of infection. It is an interesting pro-inflammatory cytokine as it has been shown to inhibit the replication of viruses such as vesicular stomatitis virus, encephalomyocarditis virus, herpes simplex virus, influenza virus and HIV-1 in specific cell lines (72)(73)(74), but also stimulates HIV-1 replication in chronically infected T-cells and promonocytic cell lines (75)(76)(77). TNF-a also plays a crucial role in both the mitogenactivated protein kinases (MAPK) and the necroptosis (programmed necrosis) pathways.…”