18th International HIV Drug Resistance Workshop Basic Principles & Clinical Implications June 9–13 2009, Fort Myers, Florida, USA

THE ROLE OF CHITINASE-3-LIKE-1 IN BACTERIAL TRANSLOCATION DURING HIV-1 INFECTION

Antivir Ther 2009; 14 Suppl 1:A9 (abstract no. 7)

AJ Smith, TW Schacker, MB Sivertson, MM Shepherd, MJ Henry-Stanley, CL Wells and AT Haase
University of Minnesota, Minneapolis, MN, USA

BACKGROUND: One hallmark pathological feature of progressive HIV-1 infection is chronic activation of the immune system. Recent evidence has implicated microbial translocation from the gastrointestinal tract as a factor driving this systemic process. However, the mechanisms underlying microbial translocation remain unclear. We have identified a gene known as chitinase-3-like-1 (CHI3L1) that may play an important role in facilitating bacterial translocation during HIV-1 infection.

METHODS: In vivo expression of CHI3L1 was observed using CHI3L1-specific antibodies in immunohistochemical and immunofluorescent analyses of gut biopsies (n=24) from HIV-1-infected individuals at various stages of disease. The induction of CHI3L1 gene expression was analysed via RT-PCR of intestinal epithelial cell lines treated with various agents. The ability of CHI3L1 to participate in microbial translocation was assayed in vitro by expressing CHI3L1 in intestinal epithelial cell lines and measuring levels of bacterial internalization. In vivo correlation analyses were performed using Pearson’s correlation coefficient (r).

RESULTS: CHI3L1 is upregulated in the gut approximately 12-fold in acute HIV-1 infection, approximately eightfold in asymptomatic and AIDS stages of disease compared with uninfected controls. CHI3L1 is expressed as an extracellular membrane protein predominantly in intestinal epithelial cells and lamina propria macrophages during viral infection. In vitro, CHI3L1 gene expression was induced by recombinant HIV-1 envelope protein and substantiated in vivo as CHI3L1 expression was correlated with HIV-1 replication (r=0.4433; P=0.01), whereby protein levels of CHI3L1 decreased in HAART patients concomitant with inhibition of viral replication. Expression of CHI3L1 in intestinal epithelial cell lines increased internalization of various microbes three to fivefold compared with cells without CHI3L1 expression. Finally, CHI3L1 expression in the gut was strongly associated with systemic immune activation in vivo as measured by the cell activation marker, Ki-67, in distal lymph nodes (r=0.8488; P<0.0001).

CONCLUSIONS: Collectively, this data provides mechanistic insight surrounding microbial translocation during HIV-1 infection. CHI3L1’s expression in the gut may facilitate bacterial translocation across an intact intestinal epithelial barrier as a means driving systemic immune activation. This data advocates continued research in this area to develop novel therapeutic targets to attenuate chronic immune activation in HIV-1 infection.

2009-06-09
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