Effects on HIV-1 replication in monocytic cells by HMGB-1

Nowak Piotr, Sonnerborg Anders. Divisions of Clinical Virology and Infectious Diseases, Karolinska Institute, Huddinge University Hospital, S-141 86, Stockholm (Sweden).

Background: The high mobility group protein (HMGB-1) is an abundant protein that is found in every cell. It binds to chromatin and takes part in the stabilization of the nucleosome complexes. Also, in the last 5 years this molecule has been found to function as an extracellular signaling protein exerting proinflammatory properties. The mechanisms reported are release of inflammatory cytokines due to stimulation of monocytes. Recently, release of HMGB-1 has been described when cells die by necrosis and, furthermore, that this release is withdrawn when cell death is triggered by apoptosis. Material and Methods: HMGB-1 was added to monocytic cell line (U1), harboring two copies of HIV-1 DNA and primary cells - monocyte derived macrophages (M/M) infected with HIV-1. The effect on the HIV replication in vitro was measured in the culture. Results: Adding extracellular HMGB-1 increased the replication of HIV-1 in monocytic cells, U1, which is an established model for studying latent HIV-1 infection. This effect was dose dependent and when the cells were treated with gluccocorticoids, the HMGB-1 stimulation of the viral production was inhibited possibly indicating the involvement of the NF-kB pathway. The opposite effect of HMGB-1 influence was seen in HIV-1 infected primary monocytic cells with ongoing viral replication. This can possibly be explained by an increased release of chemokines (RANTES, MIP-1a, MIP-1b) that are known to inhibit viral replication. The stimulatory effect of the HMGB-1 was not present when latently infected T-cells (ACH-2) were used as target cells. This data is well in line with an already described selective effect of HMGB-1 on monocytic- and lymphocytic cells. Conclusion: HMGB-1 plays a complex role in the regulation of HIV-1 replication and our data suggest that release of extracellular HMGB-1 may activate latent/low grade replicative virus in monocytes but may down-regulate the replication in highly productive infection. A similar pattern was not seen in lymphocytes.