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.
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 SIV(mac251) 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.
Animal Models & Retroviral Vaccines Section, NCI, NIH, Bethesda, Maryland, USA.
Monica
M
Vaccari
Adriano
A
Boasso
Claudio
C
Fenizia
Dietmar
D
Fuchs
Anna
A
Hryniewicz
Tia
T
Morgan
Deborah
D
Weiss
Melvin N
MN
Doster
Jean Michel
JM
Heraud
Gene M
GM
Shearer
Genoveffa
G
Franchini
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D016049:Didanosine / Q000009:adverse effects* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination / Q000009:adverse effects; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors; D008253:Macaca mulatta; D010195:Pancreatitis / Q000209:etiology* / Q000276:immunology / Q000401:mortality; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D018119:Stavudine / Q000009:adverse effects* / Q000627:therapeutic use; D014364:Tryptophan / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use
D016915:AIDS Vaccines; D019380:Anti-HIV Agents; D060908:CTLA-4 Antigen; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan; D018119:Stavudine; D016049:Didanosine