A small animal model of immune reconstitution inflammatory syndrome following antiretroviral therapy (CAM1P.159)

In HIV-infected patients with latent or subclinical tuberculosis (TB), the development of immune reconstitution inflammatory syndrome (IRIS) following restoration of T cell populations by anti-retroviral therapy (ART) can produce a life threatening inflammatory reaction. The objective of this study was to use our humanized mouse model of Mycobacterium tuberculosis ( Mtb ) and HIV co-infection to develop a small animal model of IRIS. Humanized BLT mice (HuMice) were infected i.n. with Mtb H37Rv, and following development of TB disease were given TB chemotherapy (rifampicin and isoniazid) by oral gavage. Bacteria were not detected in the lung following TB chemotherapy, but low numbers of Mtb were detected two months after stopping drug treatment, which mimics subclinical TB. When Mtb -infected and TB drug-treated HuMice were infected i.v. with HIV-1 Ada, the animals developed HIV-1 co-infection as determined by the presence of the HIV p24 capsid protein in peripheral blood by ELISA. ART was performed to reduce viral load in blood plasma and restore T lymphocyte function in animals with subclinical TB. In ongoing studies, the development of inflammatory responses, Th1 cell activation and lung pathology are being determined to understand how immune recovery, due to ART, drives inflammation in the setting of subclinical TB. This model will facilitate investigations to understand the mechanistic basis for IRIS and identify targets for host-directed therapies.