title: HIV-1 gp120 signaling through TLR4 modulates innate immune activation in human macrophages and the biology of hepatic stellate cells.
abstract: Highly active antiretroviral therapy has significantly improved the prognosis of HIV-infected subjects. However, patients treated long term still manifest increased mortality and, even with undetectable plasma viremia, often experience persistent immune activation. Furthermore, liver-related mortality is now the most common cause of non-AIDS-related death in HIV-infected individuals on highly active antiretroviral therapy through accelerated fibrosis progression. TLRs are the first line of the host response to pathogens and play an important role in human host defense against viruses through sensing of viral structural proteins. Growing evidence points to TLR4 as a key player in chronic immune activation, HIV recognition/replication, and liver fibrosis progression, suggesting that HIV triggering of TLR4 may dictate some aspects of the multifaceted AIDS pathogenesis. In this study, we provide evidence for an interplay between host TLR4 and HIV-1 gp120 in human monocyte-derived macrophages and hepatic stellate cells, leading to intracellular pathways and biologic activities that mediate proinflammatory and profibrogenic signals. Finally, we hypothesize that CCR5 and TLR4 are likely part of a common receptor cluster, as the blocking of CCR5 by specific antagonists impairs the macrophage capacity to produce chemokines in response to LPS. Chronic immune activation and liver fibrosis remain important obstacles for highly active antiretroviral therapy success. Thus, the identification of gp120-TLR4 axis as a novel determinant of immune system and hepatic stellate cell biology opens new perspectives to the management of HIV infection and disease.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; and manuela.delcorno@iss.it.
authors.forename: Manuela
authors.initials: M
authors.lastname: Del Cornò
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappon
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; and.
authors.forename: Gloria
authors.initials: G
authors.lastname: Donninelli
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; and.
authors.forename: Barbara
authors.initials: B
authors.lastname: Varano
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Marra
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy; and sandra.gessani@iss.it.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gessani
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D002478:Cells, Cultured; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000276:immunology; D055166:Hepatic Stellate Cells / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006801:Humans; D008103:Liver Cirrhosis / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology / Q000821:virology; D019713:Receptors, CCR5 / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D015699:HIV Envelope Protein gp120; D019713:Receptors, CCR5; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4
keywords: AIDS; chemokine; cytokine; migration; receptor