HIV Infection and TLR Signalling in the Liver

Abstract

Despite the availability of effective combination antiretroviral therapy (cART), liver disease is one of the leading causes of morbidity and mortality in Human Immunodeficiency Virus (HIV)-infected individuals, specifically, in the presence of viral hepatitis coinfection. HIV, a single stranded RNA virus, can bind to and activate both Toll-like receptor (TLR)7 and TLR8 in circulating blood mononuclear cells, but little is known about the effect of HIV on TLRs expressed in the liver. HIV can directly infect cells of the liver and HIV-mediated depletion of CD4+ T-cells in the gastrointestinal tract (GI tract) results in increased circulating lipopolysaccharide (LPS), both of which may impact on TLR signaling in the liver and subsequent liver disease progression. The potential direct and indirect effects of HIV on TLR signaling in the liver will be explored in this paper.

Figure 1

TLR signalling in the liver in the setting of HIV-HBV coinfection. HIV infection results in a significant increase in circulating LPS, potentially triggering an inflammatory response via activation of TLR4. ssHIV RNA can also activate TLR7 or 8 leading to an increase in NF-κB which can drive both HIV replication and production of proinflammatory cytokines and chemokines. HBV binds to and inhibits signalling through Mal/TIRAP which would inhibit proinflammatory responses in the coinfected liver. Increased LPS and/or increased hepatic apoptosis in the coinfected liver could also activate TLR9 resulting in further inflammation and HIV replication.