HIV-Infected Lymphocytes Regulate Fibronectin Synthesis by TGFβ1 Secretion

Abstract

Alterations in lymph node architecture occur with HIV infection and contribute to immunological derangements. We previously showed that matrix fibronectin stabilized HIV and increased HIV infection of PBL. We showed increased fibronectin deposition in lymph nodes of HIV-infected patients. However, we did not detect a difference in fibronectin synthesis between uninfected and infected PBL. Therefore, we hypothesized that interactions of HIV-infected cells with fibroblasts resulted in increased fibronectin deposition. We detected increased fibronectin deposition by immunofluorescence on fibroblasts cocultured with HIV-infected PBL. We also found a 6-fold increase in fibronectin mRNA levels in fibroblasts cocultured with HIV-infected PBL by real-time PCR. Furthermore, when HIV-infected PBL were added to reporter fibroblasts stably transfected with a fibronectin promoter, we found a 1.5- to 2-fold increase in promoter activity. Since conditioned medium from HIV-infected PBL also increased fibronectin promoter activity, we hypothesized that a soluble factor such as TGFβ was responsible for increased fibronectin secretion. Pretreatment of supernatant from HIV-infected PBL with a neutralizing Ab to TGFβ1 abrogated the increased fibronectin promoter activity. We confirmed that HIV-infected PBL produced increased TGFβ1 by ELISA. Using Mv1Lu reporter cells, we found a 2- to 3-fold increase in biologically active TGFβ in supernatants of HIV-infected PBL. Finally, we determined that HIV infection did not change the percentage of active TGFβ. Our data suggest that HIV-infected lymphocytes indirectly contribute to lymph node remodeling by secretion of TGFβ1, which increases fibronectin synthesis by fibroblasts.

Investigation of Plasma Biomarkers in HIV-1/HCV Mono- and Coinfected Individuals by Multiplex iTRAQ Quantitative Proteomics

“…Data shows that patients with HIV-infected lymphocytes have elevated levels of FN1 in the cells themselves; this correlation is supported by the idea that FN1 plays a critical role in stabilizing the HIV infection process (Pal and Schnapp, 2004). Although the quantity of blood cell proteins has been up regulated, the amount of FN1 will be downregulated in plasma to compensate for the increased cellular levels.…”

Leptospiral Outer Membrane Protein Induces Extracellular Matrix Accumulation through a TGF-β1/Smad-Dependent Pathway

“…In this study, we found that overexpression of the dominant negative Smad3 in HK-2 cells inhibited the Leptospira santarosai serovar Shermani OMP-induced increase of type I and type IV collagens, suggesting that Smad3, a downstream mediator of TGF-␤1, plays a pivotal role in this process. Several studies have demonstrated that infection with microorganisms, including parasite, virus, and bacterium, leads to an increase of TGF-␤1 production in different cell types (35)(36)(37). However, it is not clear that these infections can activate the TGF-␤ downstream Smad signaling.…”

Myeloid dendritic cells isolated from tissues of SIV-infected Rhesus macaques promote the induction of regulatory T cells

“…TGF-β, a cytokine known to be involved in Treg conversion, is increased in lymphatic tissues during SIV- and HIV-infection and appears to be generated by Treg present there [11, 76]. TGF-β-producing Treg may then educate DC to become tolerogenic through a phenomenon termed “infectious tolerance” [77, 78], thereby perpetuating a cycle of immune-suppression.…”