Role of Leishmania donovani and its lipophosphoglycan in CD4+ T-cell activation-induced human immunodeficiency virus replication.
Chronic 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 parasite Leishmania donovani and its major membrane constituent, lipophosphoglycan (LPG), in mediating CD4+ T-lymphocyte activation-induced HIV replication and CD4+ T-cell death. We found that Leishmania antigens 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-alpha), interleukin 2 (IL-2), and IL-6. LPG induced TNF-alpha secretion in the absence of increased expression of cellular activation markers. Moreover, in a few cases we observed that L. donovani induced HIV replication without significant cellular activation but with cytokine secretion. The rate of apoptosis was accelerated in these latently infected CD4+ T cells primed with Leishmania antigens compared to controls, and TNF-alpha production appeared to be the central event necessary for this effect. Furthermore, we demonstrate that thalidomide inhibited Leishmania-induced virus replication coupled with abrogated Leishmania-induced TNF-alpha secretion but not IL-2 or IL-6 production. Furthermore, thalidomide did not affect Leishmania-induced apoptosis. The results suggest that Leishmania and 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-alpha secretion is pivotal in this process. The immunomodulatory role of thalidomide raises interest as a potential adjuvant to reduce HIV disease progression in Leishmania-HIV coinfected individuals.
Wolday
D
D
Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
Akuffo
H
H
Demissie
A
A
Britton
S
S
D000328:Adult; D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D006028:Glycosphingolipids / Q000494:pharmacology*; D006678:HIV / Q000502:physiology*; D006801:Humans; D007893:Leishmania donovani / Q000276:immunology*; D008213:Lymphocyte Activation; D013792:Thalidomide / Q000494:pharmacology; D014779:Virus Replication
D000953:Antigens, Protozoan; D016207:Cytokines; D006028:Glycosphingolipids; C008290:lipophosphonoglycan; D013792:Thalidomide