Role ofLeishmania donovaniand Its Lipophosphoglycan in CD4+T-cell Activation-Induced Human Immunodeficiency Virus Replication
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ABSTRACTChronic immune activation by coinfecting pathogens has been suggested as a cofactor in human immunodeficiency virus (HIV) disease progression, particularly in the setting of developing countries. Here, we used in vivo-infected mononuclear cells to examine the role of the protozoan parasiteLeishmania donovaniand its major membrane constituent, lipophosphoglycan (LPG), in mediating CD4+T-lymphocyte activation-induced HIV replication and CD4+T-cell death. We found thatLeishmaniaantigens upregulated HIV replication in CD8-depleted peripheral blood mononuclear cells from asymptomatic HIV-infected donors compared to unstimulated cells.L. donovani-induced viral replication was associated with cellular proliferation, increased expression of the cellular immune activation markers CD25 and HLA-DR within the CD4+subpopulation, and enhanced secretion of tumor necrosis factor alpha (TNF-α), interleukin 2 (IL-2), and IL-6. LPG induced TNF-α secretion in the absence of increased expression of cellular activation markers. Moreover, in a few cases we observed thatL. donovaniinduced HIV replication without significant cellular activation but with cytokine secretion. The rate of apoptosis was accelerated in these latently infected CD4+T cells primed withLeishmaniaantigens compared to controls, and TNF-α production appeared to be the central event necessary for this effect. Furthermore, we demonstrate that thalidomide inhibitedLeishmania-induced virus replication coupled with abrogatedLeishmania-induced TNF-α secretion but not IL-2 or IL-6 production. Furthermore, thalidomide did not affectLeishmania-induced apoptosis. The results suggest thatLeishmaniaand its product, LPG, up-regulate HIV replication in latently infected cells through distinct antigen-specific and non-antigen-specific cellular immune activation mechanisms and that TNF-α secretion is pivotal in this process. The immunomodulatory role of thalidomide raises interest as a potential adjuvant to reduce HIV disease progression inLeishmania-HIV coinfected individuals.
