title: HIV-1 Tat exacerbates lipopolysaccharide-induced cytokine release via TLR4 signaling in the enteric nervous system.
abstract: The loss of gut epithelium integrity leads to translocation of microbes and microbial products resulting in immune activation and drives systemic inflammation in acquired immunodeficiency syndrome (AIDS) patients. Although viral loads in HIV patients are significantly reduced in the post-cART era, inflammation and immune activation persist and can lead to morbidity. Here, we determined the interactive effects of the viral protein HIV-1 Tat and lipopolysaccharide (LPS) on enteric neurons and glia. Bacterial translocation was significantly enhanced in Tat-expressing (Tat+) mice. Exposure to HIV-1 Tat in combination with LPS enhanced the expression and release of the pro-inflammatory cytokines IL-6, IL-1β and TNF-α in the ilea of Tat+ mice and by enteric glia. This coincided with enhanced NF-κB activation in enteric glia that was abrogated in glia from TLR4 knockout mice and by knockdown (siRNA) of MyD88 siRNA in wild type glia. The synergistic effects of Tat and LPS resulted in a reduced rate of colonic propulsion in Tat+ mice treated with LPS. These results show that HIV-1 Tat interacts with the TLR4 receptor to enhance the pro-inflammatory effects of LPS leading to gastrointestinal dysmotility and enhanced immune activation.
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Joy
authors: J
authors: Guedia
authors: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors: Paola
authors: P
authors: Brun
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Sukhada
authors: S
authors: Bhave
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Sylvia
authors: S
authors: Fitting
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Minho
authors: M
authors: Kang
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: William L
authors: WL
authors: Dewey
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Kurt F
authors: KF
authors: Hauser
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Hamid I
authors: HI
authors: Akbarali
mesh_terms: D000818:Animals; D018988:Bacterial Translocation / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism*; D017615:Enteric Nervous System / Q000276:immunology*; D005769:Gastrointestinal Motility; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009457:Neuroglia / Q000276:immunology; D009474:Neurons / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D054322:tat Gene Products, Human Immunodeficiency Virus