Extracellular HMGB1 is an important component contributing to tissue injury in acute and chronic inflammatory conditions. HMGB1 and its receptors RAGE, TLR2 and TLR4 have been implicated in mechanisms of many diseases, including cancer, sepsis, atherosclerosis, stroke, rheumatoid arthritis and many other inflammatory conditions. 89 Plasma levels of HMGB1 are elevated during the course of HIV-1 infection 17 and positively associated with high viral load. 90 HMGB1 can be passively released by virus-infected cells including primary CD4 T cells infected with HIV-1, and this was associated with both necrotic and apoptotic cell death. 91 HMGB1 can also be released by non-infected apoptotic CD4 T cells that die through a bystander killing process, which is mainly induced by extracellular HIV-1-encoded proteins and by HIV-1associated chronic immune activation. 46 Increased circulating HMGB1 levels detected in progressive HIV-1 infection, combined with microbial products and TLR ligands, may contribute to gut inflammation and subsequent microbial translocation, suggested to have an important role in HIV pathogenesis. 92 Microbial translocation is the leaking of normally friendly commensal bacteria from the gut -where they are usually contained -into the systemic circulation. Brenchley et al. 92 proposed that this phenomenon contributes to immune activation in patients with HIV, and thus has a causative role in the progression of the disease. Markers of microbial translocation found in the bloodstream include LPS and bacterial DNA, and the level of circulating LPS in the first year of chronic HIV infection is a strong predictor of disease progression independent of CD4 T-cell count and HIV viraemia. 93 The possible link between circulating LPS and HMGB1 levels in inflammatory conditions is suggested by following recent observations: (1) priming of macrophages with LPS induces the processing and releasing of HMGB1 in addition to IL-1b, IL-18 and TNF-a, which requires the inflammasome components ASC, caspase 1 and NALP3; 28 (2) conversely, NALP3 silencing has a protective effect in a murine model of liver ischemia-reperfusion injury, associated with decreased production of HMGB1, IL-1b, IL-18, TNF-a and IL-6; 94 (3) the resistance of caspase-1-deficient mice to LPS correlates with reduced serum HMGB1 levels. 28 (4) HMGB1 forms highly inflammatory complexes with LPS, and signals through the TLR4; 95 (5) an association of elevated circulating levels of LPS and high viral load was reported in HIV-infected patients. 90 Thus, HMGB1-LPS complexes may be important in perpetuating inflammatory amplification loops in HIV disease. Thus, HMGB1 by itself, or combined to LPS or other TLR ligand or cytokines, may induce a self-perpetuating cycle by contributing to immune activation that creates new T-cell targets for viral infection and subsequent increased rate of cell death and release of HMGB1, but also by stimulating HIV replication and viral persistence in DCs. This vicious circle may facilitate HIV disease progression and contribute to AIDS pathogenesis ( Figure 6 ).