Role of intestinal myofibroblasts in HIV-associated intestinal collagen deposition and immune reconstitution following combination antiretroviral therapy

Abstract

Objective To investigate the potential role of mucosal intestinal myofibroblasts (IMFs) in HIV and associated fibrosis in GALT. Design Profibrotic changes within the secondary lymphoid organs and mucosa has been implicated in failed immune reconstitution following effective cART. Microbial translocation is believed to be sustaining these systemic inflammatory pathways. IMFs are non-professional antigen-presenting cells with both immunoregulatory and mesenchymal functions that are ideally positioned to respond to translocating microbial antigen. Methods Duodenal biopsies obtained from patients naïve to cART underwent trichrome staining and examined for TGF-β expression. Combined immunostaining and second harmonic generation-analysis was used to determine IMF activation and collagen deposition. Confocal microscopy was performed to examine for IMF activation and TLR4 expression. Finally, primary IMF cultures were stimulated with LPS to demonstrate expression of inflammatory biomarkers. Results The expression of the fibrosis-promoting molecule, TGF-β1, is significantly increased in duodenal biopsies from HIV patients naïve to cART and negatively correlated with subsequent peripheral CD4 recovery. The TGFβ1 increases coincided with an increase in collagen deposition in duodenal mucosa in tissue area adjacent to IMFs. We also observed that IMFs expressed TLR4 and had an activated phenotype since they were positive for fibroblast activation protein. Finally, stimulation of IMFs from HIV patients with TLR4 resulted in significantly increased expression of profibrotic molecules, TGF-β1 and IL-6. Conclusions Our data support the hypothesis that activated IMFs may be among the major cells contributing to the profibrotic changes and thus, the establishment and maintenance of systemic inflammation interfering with immune reconstitution in HIV patients.

African green monkeys avoid SIV disease progression by preventing intestinal dysfunction and maintaining mucosal barrier integrity

“…Apart from loss of gut mucosal integrity, increased collagen deposition resulting in rapid destruction of LN architecture and fibrosis is also a hallmark of pathogenic HIV/SIV infections and impaired immune recovery in the gut [92,133]. We found no evidence of increased fibrosis (i.e., collagen deposition) in either the gut or LNs of SIVsab-infected AGMs, and we confirmed this result by showing stable levels of hyaluronic acid in the plasma throughout the follow-up.…”

Impaired gut junctional complexes feature late-treated individuals with suboptimal CD4+ T-cell recovery upon virologically suppressive combination antiretroviral therapy

“…Interestingly, tissue fibrosis has also been implicated in failed immune reconstitution following effective cART [71]. Although our study was not specifically designed to investigate fibrosis in the gut of INR and full responders, it is highly likely that our patients display wide tissue fibrosis, in turn further contributing to gastrointestinal damage.…”

HIV as a Cause of Immune Activation and Immunosenescence

“…This leads to collagen deposition, tissue fibrosis, and fibroblastic reticular cell network loss within the parafollicular T-cell zone of lymph nodes [ 89 – 91 ]. The interaction between mucosal intestinal myofibroblasts (IMFs) and LPS also leads to an increase in the soluble mediators of fibrogenesis (IL-6 and TGF- β 1), which directly increase collagen deposition by IMFs [ 92 ]. This may contribute to the disproportionate depletion of CD4 + T-cells in the GIT [ 90 ].…”