Circulating levels of HMGB1 are correlated strongly with MD2 in HIV-infection: Possible implication for TLR4-signalling and chronic immune activation

Abstract

Progressive HIV infection is characterized by profound enterocyte damage, microbial translocation and chronic immune activation. We aimed to test whether High Mobility Group Box protein 1(HMGB1), a marker of cell death, alone, or in combination with LPS, might contribute to HIV-associated immune activation and progression. Altogether, 29 untreated HIV-infected individuals, 25 inflammatory bowel disease (IBD) patients and 30 controls were included. HIV-infected patients had lower plasma LPS levels than IBD patients, but higher levels of soluble CD14 and Myeloid Differentiation (MD) 2, which interacts with TLR4 to initiate LPS-signalling. Furthermore, plasma levels of HMGB1 and MD2 were correlated directly within the HIV-infected cohort (r = 0.89, P < 0.001) and the IBD-cohort (r = 0.85, P < 0.001), implying HMGB1 signalling through the MD2/TLR4-pathway. HMGB1 and LPS, although not inter-correlated, were both moderately (r = 0.4) correlated with CD38 density on CD8+ T cells in HIV progressors. The highest levels of CD38 density and MD2 were found in progressors with plasma levels of both LPS and HMGB1 above the fiftieth percentile. Our results could imply that, in some patients, immune activation is triggered by microbial translocation, in some by cell death and in some by HMGB1 in complex with bacterial products through activation of the MD2/TLR4-pathway.

Soluble Markers of the Toll-Like Receptor 4 Pathway Differentiate between Active and Latent Tuberculosis and Are Associated with Treatment Responses

“…LPS concentrations in plasma were then analyzed in duplicates by the LAL colorimetric assay according to the manufacturer’s instructions with the following modifications: plasma samples were diluted 10-fold to avoid interference with background color and preheated to 68°C for 12 minutes prior to analyses to dissolve immune complexes as previously described [29]. Test samples were mixed with the LAL supplied in the test kit and incubated at 37°C for 10 minutes.…”

“…Soluble (s) CD14 serves as a receptor for the complex of LPS and LPS binding protein (LBP) and plays a central role by transferring LPS to MD-2, thus activating immune responses to bacterial endotoxins [22], [26]. Elevated levels of sCD14 are associated with various systemic inflammatory diseases including TB [27], and increased levels of MD-2 have been detected in plasma from patients with severe sepsis as well as in HIV infection [28], [29]. It has been shown that during anti-TB treatment the levels of sCD14 slowly decline [27] and the levels of LBP are lower in treated compared to untreated TB patients [30].…”

HMGB1 in health and disease

“…Despite advances, HIV remains a major public health challenge since it was discovered in the early 1980s. Plasma HMGB1 levels are elevated and related to viral load and MD2/TLR4 in patients with HIV infection (Nowak et al, 2007; Troseid et al, 2013; Troseid et al, 2010). Intracellular HMGB1 inhibits long terminal repeat (LTR)-mediated HIV transcription (Naghavi et al, 2003), whereas extracellular HMGB1 has a dual role in the regulation of HIV transcription, depending on the stage of infection and type of cell (Cassetta et al, 2009; Nowak et al, 2006).…”

Microbial Translocation and Cardiometabolic Risk Factors in HIV Infection

“…51,52 Recently, it was shown that systemic LPS levels and markers of TLR4 activation (MD-2 and soluble CD14; sCD14) in chronic HIV infection are increased. 53 Activated TLRs in turn activate transcription factors that lead to de novo production of proinflammatory cytokines such as interleukin (IL)-1b, IL-6, and tumor necrosis factor (TNF). 42,54 Enhanced microbial translocation has been associated with activated CD4 + and CD8 + T cell phenotypes, 42,55,56 and accumulating evidence suggests that microbial translocation is a predictor of disease progression, poor immune restoration, and non-AIDS morbidity in HIV infection.…”