High Mobility Group Box Protein-1 in HIV-1 Infection: Connecting Microbial Translocation, Cell Death and Immune Activation

Chronic immune activation driven by microbial translocation from a damaged gut plays a fundamental role in HIV-1 progression. However, the exact link between a leaky gut and immune activation remains to be established. A growing body of evidence suggests that high mobility group box protein-1 (HMGB1) may be involved in this process. HMGB1 is a DNA binding protein present in every nucleated cell, which might be actively secreted to the extracellular milieu by activated cells or passively released from damaged or dying cells. The biological effect depends on its ability to form complexes: HMGB1 alone signals through the receptor of advanced glycosylated end products (RAGE) and promotes regeneration and repair, whereas HMGB1 in complex with bacterial products signal via toll like receptors (TLRs) and promotes immune activation. Plasma levels of HMGB1 are elevated in HIV-1 infected patients and reduced by antiretroviral therapy. The protein might be released from necrotic and apoptotic HIV-1 infected cells. HMGB1 may stimulate or inhibit HIV-1 replication in vitro, depending on the stage of infection, type of cell and purity of the protein: The protein has been suggested to reduce viral replication by interfering with viral entry in acute infection and to increase viral replication in latently infected cells. Finally, HMGB1 in combination with microbial products/TLR ligands seems to be associated with increased viral replication in vitro and in vivo.