title: Immune activation and regulation in simian immunodeficiency virus-Plasmodium fragile-coinfected rhesus macaques.
abstract: Human immunodeficiency virus (HIV) is characterized by immune activation, while chronic malaria is associated with elevated interleukin-10 (IL-10) levels. How these apparently antagonizing forces interact in the coinfected host is poorly understood. Using a rhesus macaque model of simian immunodeficiency virus (SIV)-Plasmodium fragile coinfection, we evaluated how innate immune effector cells affect the balance between immune activation and regulation. In vitro Toll-like receptor (TLR) responses of peripheral blood myeloid dendritic cells (mDC) and monocytes were temporarily associated with acute parasitemic episodes and elevated plasma IL-10 levels. Prolonged infection resulted in a decline of mDC function. Monocytes maintained TLR responsiveness but, in addition to IL-12 and tumor necrosis factor alpha, also produced IL-10. Consistent with the role of spleen in the clearance of parasite-infected red blood cells, coinfected animals also had increased splenic IL-10 mRNA levels. The main cellular source of IL-10 in the spleens of coinfected animals, however, was not splenic macrophages but T cells, suggesting an impairment of adaptive immunity. In contrast to those in spleen, IL-10-positive cells in axillary lymph nodes of coinfected animals were predominantly mDC, reminiscent of the immunosuppressive phenotype of peripheral blood mDC. Concurrent with IL-10 induction, however, SIV infection promoted elevated systemic IL-12 levels. The continuously increasing ratio of plasma IL-12 to IL-10 suggested that the overall host response in SIV-P. fragile-coinfected animals was shifted toward immune activation versus immune regulation. Therefore, SIV-P. fragile coinfection might be characterized by earlier manifestation of immune dysfunction and exhaustion than that of single-pathogen infections. This could translate into increased morbidity in HIV-malaria-coinfected individuals.
authors.affiliation: California National Primate Research Center, University of California at Davis, Davis, California, USA.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Trott
authors.forename: Amy
authors.initials: A
authors.lastname: Richardson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hudgens
authors.forename: Kristina
authors.initials: K
authors.lastname: Abel
mesh_terms: D000818:Animals; D060085:Coinfection / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D006790:Host-Parasite Interactions / Q000235:genetics / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism; D008221:Lymphoid Tissue / Q000276:immunology; D008253:Macaca mulatta; D008288:Malaria / Q000150:complications* / Q000235:genetics / Q000276:immunology*; D008297:Male; D009000:Monocytes / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000150:complications* / Q000235:genetics / Q000276:immunology*; D015302:Simian Immunodeficiency Virus; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D051193:Toll-Like Receptors; D016753:Interleukin-10; D018664:Interleukin-12