STAPHYLOCOCCAL SUPERANTIGENS ACTIVATE HIV-1 REPLICATION IN NATURALLY INFECTED MONOCYTES

OBJECTIVES: To study the effects of microbial superantigens, Staphylococcal exotoxins (SE), on HIV replication in monocytes following binding to and signalling through major histocompatibility complex (MHC) class II molecules. METHODS: We investigated the effects of SE on HIV replication and monokine production in three different in vitro models of monocyte culture: chronically infected monocytic cell line U1, acute infection of normal monocytes by different HIV-1 strains, and naturally-infected monocytes from seropositive patients. p24 antigen, interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha production was measured by specific enzyme-linked immunosorbent assay (ELISA). RESULTS: Staphylococcal enterotoxin B and toxic shock syndrome toxin-1 (1-1000 ng/ml) are powerful inducers of HIV-1 expression in U1 cells pretreated with granulocyte macrophage colony stimulating factor. SE induce viral replication in short-term cultures (days 6-21) of monocytes infected in vitro by HIVBa-L, HIVLAI, or naturally infected in vivo. Induction of HIV expression requires direct interactions of SE with MHC class II molecules but not T-cell receptor binding and T-cell-monocyte contact. Anti-TNF-alpha and anti-IL-6 neutralizing monoclonal antibodies inhibit by over 61% SE-induced HIV replication. CONCLUSIONS: Using SE we have linked two important pathways for the regulation of HIV replication in monocytes, namely signalling through MHC class II molecules and monokine production potentially mediated by induction of the pleiotropic cellular transcription factor NF-kappa B. In HIV-infected patients bacterial infections are common and could be an important cofactor in the immunopathogenesis of AIDS by inducing HIV replication in latently infected monocytes. Their prevention might emerge as beneficial in these patients.