Human immunodeficiency virus (HIV) infection is associated with immune activation, CD4 (-T-cell loss, and a progressive decline of immune functions. Antiretroviral therapy (ART) only partially reverses HIV-associated immune dysfunction, suggesting that approaches that target immune activation and improve virus-specific immune responses may be needed. We performed a preclinical study in rhesus macaques infected with the pathogenic simian immunodeficiency virus SIVmac251 and treated with ART. We tested whether vaccination administered together with cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) blockade and treatment with the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-D-tryptophan (D-1mT), decreased immune activation and improved vaccine efficacy. The treatment did not augment vaccine immunogenicity; rather, it dramatically increased ART-related toxicity, causing all treated animals to succumb to acute pancreatitis and hyperglycemic coma. The onset of fulminant diabetes was associated with severe lymphocyte infiltration of the pancreas and complete loss of the islets of Langerhans. Thus, caution should be used when considering approaches aimed at targeting immune activation during ART.

Fatal pancreatitis in simian immunodeficiency virus SIV mac251-infected macaques treated with 2',3'-dideoxyinosine and stavudine following cytotoxic-T-lymphocyte-associated antigen 4 and indoleamine 2,3-dioxygenase blockade / M. Vaccari, A. Boasso, C. Fenizia, D. Fuchs, A. Hryniewicz, T. Morgan, D. Weiss, M.N. Doster, J.M. Heraud, G.M. Shearer, G. Franchini. - In: JOURNAL OF VIROLOGY. - ISSN 0022-538X. - 86:1(2012), pp. 108-113. [10.1128/JVI.05609-11]

Fatal pancreatitis in simian immunodeficiency virus SIV mac251-infected macaques treated with 2',3'-dideoxyinosine and stavudine following cytotoxic-T-lymphocyte-associated antigen 4 and indoleamine 2,3-dioxygenase blockade

M. Vaccari
Primo
;
C. Fenizia;
2012

Abstract

Human immunodeficiency virus (HIV) infection is associated with immune activation, CD4 (-T-cell loss, and a progressive decline of immune functions. Antiretroviral therapy (ART) only partially reverses HIV-associated immune dysfunction, suggesting that approaches that target immune activation and improve virus-specific immune responses may be needed. We performed a preclinical study in rhesus macaques infected with the pathogenic simian immunodeficiency virus SIVmac251 and treated with ART. We tested whether vaccination administered together with cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) blockade and treatment with the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-D-tryptophan (D-1mT), decreased immune activation and improved vaccine efficacy. The treatment did not augment vaccine immunogenicity; rather, it dramatically increased ART-related toxicity, causing all treated animals to succumb to acute pancreatitis and hyperglycemic coma. The onset of fulminant diabetes was associated with severe lymphocyte infiltration of the pancreas and complete loss of the islets of Langerhans. Thus, caution should be used when considering approaches aimed at targeting immune activation during ART.
AIDS Vaccines; Animals; Anti-HIV Agents; CTLA-4 Antigen; Didanosine; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Macaca mulatta; Pancreatitis; Simian Immunodeficiency Virus; Stavudine; Tryptophan; Immunology; Virology
Settore MED/04 - Patologia Generale
http://jvi.asm.org/content/86/1/108.full.pdf
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/485005
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