Infusion of HIV-1 Nef-expressing astrocytes into the rat hippocampus induces enteropathy and interstitial pneumonitis and increases blood–brain-barrier permeability

Autoři: Jocelyn Rivera aff001;  Raymond A. Isidro aff002;  Raisa Y. Loucil-Alicea aff002;  Myrella L. Cruz aff002;  Caroline B. Appleyard aff002;  Angel A. Isidro aff002;  Gladys Chompre aff003;  Krystal Colon-Rivera aff001;  Richard J. Noel, Jr. aff002
Působiště autorů: HIV-1 Immunopathogenesis Laboratory, The Wistar Institute, Philadelphia, PA, United States of America aff001;  Department of Basic Sciences, Ponce Health Sciences University, Ponce Research Institute, Ponce, Puerto Rico, United States of America aff002;  Department of Biology, Pontifical Catholic University of Puerto Rico, Ponce, Puerto Rico, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225760


Even though HIV-1 replication can be suppressed by combination antiretroviral therapy (cART) inflammatory processes still occur, contributing to comorbidities. Comorbidities are attributed to variety of factors, including HIV-1 mediated inflammation. Several HIV-1 proteins mediate central nervous system (CNS) inflammation, including Nef. Nef is an early HIV-1 protein, toxic to neurons and glia and is sufficient to cause learning impairment similar to some deficits observed in HIV-1 associated neurocognitive disorders. To determine whether hippocampal Nef expression by astrocytes contributes to comorbidities, specifically peripheral inflammation, we infused Sprague Dawley rats with GFP- (control) or Nef-transfected astrocytes into the right hippocampus. Brain, lung, and ileum were collected postmortem for the measurement of inflammatory markers. Increased blood-brain-barrier permeability and serum IL-1β levels were detected in the Nef-treated rats. The lungs of Nef-treated rats demonstrated leukocyte infiltration, macrophage upregulation, and enhanced vascular permeability. Ileal tissue showed reactive follicular lymphoid hyperplasia, increased permeability and macrophage infiltration. The intracerebroventricular application of IL-1 receptor antagonist reduced infiltration of immune cells into ileum and lung, indicating the important role of IL-1β in mediating the spread of inflammation from the brain to other tissues. This suggests that localized expression of a single viral protein, HIV-1 Nef, can contribute to a broader inflammatory response by upregulation of IL-1β. Further, these results suggest that Nef contributes to the chronic inflammation seen in HIV patients, even in those whose viremia is controlled by cART.

Klíčová slova:

Astrocytes – Gastrointestinal tract – Hippocampus – HIV-1 – Ileum – Inflammation – Macrophages – Tight junctions


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