32 The association of HSCs with lymphocytes in hepatitis, their positioning below the fenestrated sinusoidal endothelium, and recent demonstration of their direct interaction with lymphocytes in vivo by way of confocal microscopy makes this interaction even more likely.33, 34 Moreover, studies have suggested35 that cell-associated HIV-1 may be internalized into CD4+ T cells, resulting in a much more efficient http://www.selleckchem.com/products/Romidepsin-FK228.html infection than cell-free
virus, further highlighting the importance of our findings. Future studies will address whether HIV-infected HSCs may elicit proliferative responses in specific subsets of lymphocytes, in addition to promoting lymphocyte infiltration by secretion of chemokines such as MCP-1. Lastly, HSCs may provide an important intrahepatic source of HIV proteins (such as the envelope protein gp120) that have been shown to elicit biologic responses in neighboring cells such as hepatocytes.27, 29 Moreover, HIV gp120, has been shown to modulate HSC responses in vitro in a receptor-dependent manner.10, 11 Whether levels used for in vitro studies reflect physiologically relevant tissue levels and whether viral protein is derived
from autocrine sources (HSCs) or paracrine sources (Kupffer cells, DCs) is not clear. Our results suggest that viral entry into HSCs occurs predominantly independent of CD4, CXCR4, and CCR5. Despite the lack of a Cabozantinib clear mechanism of entry, HSCs support HIV infection and gene expression. Potential mechanisms of CD4-independent pathways for entry include the use of alternative receptors such as C-type lectins, as
has been described for other cell types such as DCs, as well as receptor-independent endocytosis13; each will be explored in future studies. L-NAME HCl A compelling question arises from our findings: “Why don’t patients monoinfected with HIV develop inflammation and fibrosis if HIV can infect HSCs and stimulate collagen I and MCP-1 expression?” In this study, we used either a moderately activated cell line (LX-2) or passage #3–activated HSCs. The phenotype of these cells changes with activation, including increased expression of cell-surface receptors and changes in the cytoskeleton. The ability for HSCs to act as APCs has only been demonstrated in activated HSCs. Preliminary work in our laboratory suggests that quiescent stellate cells are not infectable by HIV. Therefore, we hypothesize that initial injury from HCV, or from other etiologies, serves as an initiating signal to activate HSCs, which creates a permissive environment for the effects of HIV on HSCs. Typically chronic HCV infection precedes HIV infection in coinfected individuals, further supporting this hypothesis.