High Mobility Group Box 1 (HMGB1) and HIV-Associated Kaposi’s Sarcoma in Africa

Abstract

Other than Kaposi’s sarcoma-associated herpesvirus (KSHV) and CD4+ T cell lymphopenia, the mechanisms responsible for KS are poorly understood. Additional mechanisms must exist in sub-Saharan Africa given that only a minority of individuals with advanced AIDS in that setting develop KS despite the high prevalence KSHV. High mobility group box 1 (HMGB1) protein is a host transcriptional regulator that promotes cell proliferation. It is actively secreted by senescent cells (resulting in decreased transcriptional activity and cell proliferation). HMGB1 is known to interact with KSHV in vitro. Binds to KSHV latency-associated nuclear antigen (LANA) and stimulates replication and transcriptional activator (RTA) transactivation, facilitating KSHV replication. May also block p53-dependent secretion of HMGB1, thereby increasing intracellular HMGB1 levels even in the setting of senescence. Increased secretion of HMGB1 (e.g., higher plasma levels) secondary to immune activation/senescence might be associated with: Increased risk of KS to the extent it reflects inflammation and decreased immune surveillance. Decreased risk of KS to the extent it suppresses KSHV replication andspindle cell proliferation.