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Gut Epithelium is an Early Target of the Virus in the SIV Model of AIDS
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Reported by Jules Levin
CROI 2012March 5-8 Seattle WA
Lauren A. HIrao1, Irina Grishna1, Sam Sankaran-Walters1, Monsicha Somrit2, William Hu1, Holland Cheng2 and Satya Dandekar1
Departments of Medical Microbiology & Immunology1 and Molecular and Cellular Biology2, University of California, Davis, CA; Department of Molecular & Integrative Physiology 2
Abstract
Background: The effect of CD4+ T cell depletion on gut mucosal barrier integrity and the functional impairment of mucosal immune responses in chronic HIV infection have been well studied. However less is known about the effect of HIV on the gut mucosa prior to CD4+ T cell depletion.
Methods: To address the early effects of HIV on the gut epithelium we utilized a novel in vivo intestinal loop procedure in the SIV rhesus macaque model of HIV infection. Macaques were intravenously infected with SIVmac251 for 2.5 days (SIV+, n=5) and subsequently underwent ileal loop surgery. SIV-negative animals (n=5) served as controls. Loops were inoculated with either pathogenic (Salmonella serovar enterica typhimurium) or commensal (Lactobacillus plantarum) microbes for five hours to assess any changes in the gut mucosal response by early SIV infection. Mucosal immune responses were assessed by flow cytometry and quantitative real time PCR. Changes in the mucosal epithelium were assessed by immunohistochemistry and electron microscopy.
Results: SIV infection did not change or diminish mucosal immune responses to pathogenic bacteria as determined by microarray and real time PCR analysis. Flow cytometry of the CD4+ T cell response to Salmonella did not differ significantly between SIV+ macaques and healthy controls. In contrast, SIV infection resulted in a significant increase in the Th17 response to Lactobacillus compared to uninfected controls (p=0.045, 2 tailed t-test). Microarray analysis also revealed changes in tight junction proteins and chemotaxis in response to Lactobacillus in SIV+ animals. EM analysis also demonstrated that Lactobacillus inoculation lead to enhancement of the barrier integrity as observed by decreases in the paracellular space in healthy controls. However, this enhancement was not observed in SIV+ animals, suggesting that Lactobacillus could not compensate for SIV-induced changes in the epithelium.
Conclusions: We observed modification of the gut barrier integrity after just 2.5 days of SIV infection. In addition to altering the physical barrier, SIV induced an aberrant Th17 response to commensal bacteria. These early events may have a significant impact on subsequent immune dysfunction and chronic immune activation.
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