T-cell reconstitution during murine acquired immunodeficiency syndrome (MAIDS) produces neuroinflammation and mortality in animals harboring opportunistic viral brain infection

Abstract

BackgroundHighly active antiretroviral therapy (HAART) restores inflammatory immune responses in AIDS patients which may unmask previous subclinical infections or paradoxically exacerbate symptoms of opportunistic infections. In resource-poor settings, 25% of patients receiving HAART may develop CNS-related immune reconstitution inflammatory syndrome (IRIS). Here we describe a reliable mouse model to study underlying immunopathological mechanisms of CNS-IRIS.MethodsUtilizing our HSV brain infection model and mice with MAIDS, we investigated the effect of immune reconstitution on MAIDS mice harboring opportunistic viral brain infection. Using multi-color flow cytometry, we quantitatively measured the cellular infiltrate and microglial activation.ResultsInfection with the LP-BM5 retroviral mixture was found to confer susceptibility to herpes simplex virus (HSV)-1 brain infection to normally-resistant C57BL/6 mice. Increased susceptibility to brain infection was due to severe immunodeficiency at 8 wks p.i. and a marked increase in programmed death-1 (PD-1) expression on CD4+ and CD8+ T-cells. Both T-cell loss and opportunistic brain infection were associated with high level PD-1 expression because PD-1-knockout mice infected with LP-BM5 did not exhibit lymphopenia and retained resistance to HSV-1. In addition, HSV-infection of MAIDS mice stimulated peripheral immune cell infiltration into the brain and its ensuing microglial activation. Interestingly, while opportunistic herpes virus brain infection of C57BL/6 MAIDS mice was not itself lethal, when T-cell immunity was reconstituted through adoptive transfer of virus-specific CD3+ T-cells, it resulted in significant mortality among recipients. This immune reconstitution-induced mortality was associated with exacerbated neuroinflammation, as determined by MHC class II expression on resident microglia and elevated levels of Th1 cytokines in the brain.ConclusionsTaken together, these results indicate development of an immune reconstitution disease within the central nervous system (CNS-IRD). Experimental immune reconstitution disease of the CNS using T-cell repopulation of lymphopenic murine hosts harboring opportunistic brain infections may help elucidate neuroimmunoregulatory networks that produce CNS-IRIS in patients initiating HAART.

Early suppressive antiretroviral therapy in HIV infection is associated with measurable changes in the corpus callosum

“…Many other ART formulations have demonstrated a capacity for neurotoxicity as well; a systematic analysis of in vitro effects of 15 antiretroviral compounds, including nucleoside reverse transcriptase inhibitors (NRTIs), NNRTIs and protease inhibitors (PIs) on neurons found a wide range of neurotoxic mechanisms, such as mitochondrial toxicity, with the ultimate endpoint of neuronal dysfunction (Robertson et al 2012). Alternatively, neuroinflammation in the CC may be secondary to the immune reconstitution following ART initiation, which has been observed in animal models (Mutnal et al 2013). …”

Morphine increases hippocampal viral load and suppresses frontal lobe CCL5 expression in the LP-BM5 AIDS model

“…Peripherally, LP-BM5 is marked by splenomegaly, lymphadenopathy, and hypergammaglobulinemia similar to HIV-1. Suppressed B- and T-cell responses paired with a loss of CD4 + T-cell function induce the HIV-1-like state termed murine AIDS (Li and Green, 2006); recently, Mutnal et al observed a profound loss of circulating CD4 + and CD8 + T-cells in LP-BM5 animals, similar to HIV-1 patients (Mutnal et al, 2013). Altogether, LP-BM5/MAIDS offers the opportunity to explore morphine’s effects within the context of an immunodeficiency-inducing virus which infiltrates the CNS, infects glial cells, and produces established effects on cognitive function.…”

Innate and Adaptive Cellular Immune Responses toMycobacterium tuberculosisInfection

“…IFN-g production by the reconstituting CD4 T cells, which is normally required for containment of mycobacterial infection, is a major mediator of the disease in this setting. Models of IRIS associated with other microbial infections (Roths et al 1990;Sidman 1992, 1993;Bhagwat et al 2006;Mutnal et al 2013) have also found that in the setting of immune reconstitution, CD4 T cells can mediate severe immunopathology. Collectively, the data from studies of IRIS in HIV-coinfected individuals and the experimental animal model data strongly support the hypothesis that IRIS in humans is mediated by CD4 T cells and provide another example of CD4 T-cell-mediated pathology in mycobacterial infection.…”