Extracellular high mobility group box-1 inhibits R5 and X4 HIV-1 strains replication in mononuclear phagocytes without induction of chemokines and cytokines

Luca Cassetta, Orazio Fortunato, Leda Adduce, Chiara Rizzi, Julia Hering, Patrizia Rovere-Querini, Marco Emilio Bianchi, Massimo Alfano, Guido Poli

Research output: Contribution to journalArticlepeer-review

Abstract

OBJECTIVE: High mobility group box-1 (HMGB1) is a nuclear chromatin protein. Furthermore, it induces chemotaxis and inflammation once released in the extracellular milieu, and it has been reported to upregulate, but also to inhibit HIV-1 replication in different cell types. We here investigated the potential role of extracellular HMGB1 in both R5 and X4 HIV-1 replication in primary human monocyte-derived macrophages (MDM) and U937 promonocytic cells, respectively.

DESIGN: MDM or U937 cells were infected with R5 and X4 HIV-1 strains, respectively, in the presence or absence of endotoxin-free recombinant (r) HMGB1 or necrotic cell supernatants either containing or depleted of endogenous HMGB1.

METHODS: HIV replication was measured by means of virion-associated reverse transcriptase activity in culture supernatants and cell-associated viral protein expression. Cytokine and chemokine production were measured by enzyme-linked immunosorbent assay; cell surface expression of CD4, CC chemokine receptor 5, receptor for advanced glycation end-products, Toll-like receptor-2 and Toll-like receptor-4 were analyzed by flow cytometry.

RESULTS: Both rHMGB1 and necrotic cell supernatant-associated HMGB1 inhibited replication of R5 HIV-1 in MDM. Surprisingly enough, no upregulation of CC chemokine receptor 5-binding chemokines or of other chemokines and cytokines was observed in rHMGB1-stimulated MDM. HMGB1 also induced chemotaxis and strongly inhibited the replication of X4 HIV-1 in the 'Minus' subset of U937 cell clones expressing high levels of putative HMGB1 receptors (receptor for advanced glycation end-products, Toll-like receptors 2 and 4).

CONCLUSION: Extracellular HMGB1 is a potent inhibitor of both R5 and X4 HIV-1 replication in mononuclear phagocytic cells without inducing the release of HIV-Modulatory chemokines or cytokines.

Original languageEnglish
Pages (from-to)567-77
Number of pages11
JournalAIDS
Volume23
Issue number5
DOIs
Publication statusPublished - 13 Mar 2009

Keywords

  • Animals
  • Anti-HIV Agents/pharmacology
  • Cells, Cultured
  • Chemokines/biosynthesis
  • Chemotaxis/drug effects
  • Cytokines/biosynthesis
  • Drug Evaluation, Preclinical/methods
  • HIV Infections/immunology
  • HIV-1/drug effects
  • HMGB1 Protein/pharmacology
  • Humans
  • Macrophages/drug effects
  • Mice
  • Monocyte-Macrophage Precursor Cells/drug effects
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic/metabolism
  • Recombinant Proteins/pharmacology
  • Toll-Like Receptor 2/metabolism
  • Toll-Like Receptor 4/metabolism
  • U937 Cells
  • Virus Replication/drug effects

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