Immune reconstitution inflammatory syndrome (IRIS) has emerged as a major clinical complication in the management of HIV infection following the initiation of combination antiretroviral therapy (cART). IRIS is most commonly seen in patients with severe T cell lymphopenia at the initiation of treatment, often in the presence of an opportunistic infection. cART-induced reversal of lymphopenia restores host defense, but the T- cell repertoire that comes back is often of limited diversity and hyper-responsive to particular antigens due to differential expansion of specific memory T-cells. A wide variety of opportunistic pathogens have been associated with IRIS and heterogeneous clinical manifestations are observed. However, independent of the underlying pathogen or even in the absence of identifiable opportunistic infection, IRIS is characterized by excessive immune activation with elevated frequencies of reconstituting activated T-cells. Immune recovery which specifically attacks the brain is termed central nervous system (CNS)-IRIS and it is particularly challenging due to its clinical severity. Still, the neuroimmunopathogenic mechanisms resulting in CNS-IRIS are poorly understood. Results obtained in our laboratory over the previous funding period of this grant have shown that brain-infiltrating, virus-specific T lymphocytes from the peripheral immune system activate resident microglial cells, including those in widespread areas distal to focal viral infection. Building upon these findings, the central hypothesis to be tested in this competitive renewal application is that replenished yet dysregulated T-lymphocytes drive CNS-immune reconstitution disease (IRD) by providing signals which promote hyper-activation of resident microglia and the overproduction of neurotoxic mediators. In the proposed studies, we will first determine whether T-cell reconstitution of lymphopenic mice harboring herpesvirus brain infection hyper-activates resident microglial cells. This will be achieved through adoptive transfer of CD3(+) T-cells into lymphopenic animals followed by assessment of microglial activation. We will then determine how Foxp3(+) regulatory T-cell (Treg) dysregulation contributes to CNS-IRD. These studies will employ Foxp3-DTR (diphtheria toxin receptor) expressing transgenic mice to determine the effect of depleting Tregs from CD3(+) T-cells prior to adoptive transfer into infected, lymphopenic animals. The final set of experiments will determine mechanisms by which T-cell reconstitution potentiates neurodegeneration. Identification of the precise interactions between T lymphocytes and microglia which drive hyperactive neuroimmune responses is vitally important to the field of HIV medicine. Novel therapeutic approaches (e.g., Treg immunotherapy) which target distinct neuropathogenic pathways are urgently needed. However, the mechanisms to target are still poorly understood because they are difficult to address through clinical studies. In this application, we propose to fill this gap in knowledge by studying experimental CNS-IRD using T-cell repopulation of lymphopenic murine hosts harboring opportunistic viral brain infection.

Public Health Relevance

Immune reconstitution inflammatory syndrome (IRIS) is the paradoxical deterioration of clinical status seen in patients after initiation of antiretroviral thrapy and it has emerged as a major complication in contemporary management of HIV infection. IRIS which involves the central nervous system (i.e., CNS-IRIS) is particularly challenging due to its clinical severity, frequently resulting in serious neurologic disability or death. The neuroimmunopathogenic mechanisms resulting in this disease are still poorly understood because they are difficult to address through clinical studies. Elucidation of the precise mechanisms which drive this syndrome is vitally important to the field of HIV medicine, and novel therapeutic approaches which more specifically target these neuropathogenic pathways are urgently needed.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-AARR-C (03))
Program Officer
Joseph, Jeymohan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Minnesota Twin Cities
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Hu, Shuxian; Rotschafer, Jessica H; Lokensgard, James R et al. (2014) Activated CD8+ T lymphocytes inhibit neural stem/progenitor cell proliferation: role of interferon-gamma. PLoS One 9:e105219
Schachtele, Scott J; Hu, Shuxian; Sheng, Wen S et al. (2014) Glial cells suppress postencephalitic CD8+ T lymphocytes through PD-L1. Glia 62:1582-94
Mutnal, Manohar B; Schachtele, Scott J; Hu, Shuxian et al. (2013) T-cell reconstitution during murine acquired immunodeficiency syndrome (MAIDS) produces neuroinflammation and mortality in animals harboring opportunistic viral brain infection. J Neuroinflammation 10:98
Hu, Shuxian; Sheng, Wen S; Schachtele, Scott J et al. (2011) Reactive oxygen species drive herpes simplex virus (HSV)-1-induced proinflammatory cytokine production by murine microglia. J Neuroinflammation 8:123
Schachtele, Scott J; Hu, Shuxian; Little, Morgan R et al. (2010) Herpes simplex virus induces neural oxidative damage via microglial cell Toll-like receptor-2. J Neuroinflammation 7:35
El Ghazi, Issam; Sheng, Wen S; Hu, Shuxian et al. (2010) Changes in the NMR metabolic profile of human microglial cells exposed to lipopolysaccharide or morphine. J Neuroimmune Pharmacol 5:574-81
Armien, Anibal G; Hu, Shuxian; Little, Morgan R et al. (2010) Chronic cortical and subcortical pathology with associated neurological deficits ensuing experimental herpes encephalitis. Brain Pathol 20:738-50
Marques, Cristina P; Cheeran, Maxim C-J; Palmquist, Joseph M et al. (2008) Prolonged microglial cell activation and lymphocyte infiltration following experimental herpes encephalitis. J Immunol 181:6417-26
Aravalli, Rajagopal N; Hu, Shuxian; Lokensgard, James R (2008) Inhibition of toll-like receptor signaling in primary murine microglia. J Neuroimmune Pharmacol 3:5-11
Marques, Cristina P; Cheeran, Maxim C-J; Palmquist, Joseph M et al. (2008) Microglia are the major cellular source of inducible nitric oxide synthase during experimental herpes encephalitis. J Neurovirol 14:229-38

Showing the most recent 10 out of 14 publications