Stage-specific effects of Plasmodium falciparum- derived hemozoin on blood mononuclear cell TNF-α regulation and viral replication

The molecular immunological interactions between HIV and malaria are largely undefined. Since tumor necrosis factor (TNF)-alpha is elevated during acute malaria and increases with HIV-1 disease progression, TNF-alpha production may be an important mediator for interactions between malaria and HIV-1. To examine the stage-specific immunological interactions between HIV and malaria, peripheral blood mononuclear cells (PBMC) and CD14 cells were isolated and cultured from rhesus macaques at different stages of SIV infection. Cultures were stimulated with lipopolysaccharide (LPS) and interferon (IFN)-gamma in the presence of Plasmodium falciparum-derived hemozoin (Hz) or synthetic Hz (sHz). TNF-alpha transcripts and soluble protein were examined by real time reverse transcription-PCR and ELISA, respectively. The effects of Hz on viral replication were determined by measurement of p27 antigen with varying concentrations of TNF-alpha neutralizing antibodies. Hz and sHz significantly increased LPS- and IFN-gamma-induced TNF-alpha protein and transcripts in PBMC from animals with late stage SIV infection (i.e., AIDS). Hz and sHz also induced high levels of sustained TNF-alpha transcripts in PBMC from the AIDS group. During the late stage of disease, CD14 cells were the primary source of TNF-alpha production. Stimulation of PBMC with Hz and sHz significantly increased viral replication that was dose-dependently reduced by the addition of TNF-alpha neutralizing antibodies. Hz promotes high levels of TNF-alpha production from PBMC during AIDS and increases viral replication in SIV-infected animals.