Effective highly active antiretroviral therapy (HAART) reduces HIV RNA levels in cerebrospinal fluid (CSF), as well as in plasma, and has produced profound improvements in health and longevity. However, neurological complications continue to increase in prevalence as patients with the disease live longer and cognitive impairment remains one of the most feared complications;even in patients with systemically well-controlled virus. In patients receiving HAART, neuroimmune activation has been shown to persist long after reduction of viral loads. Hence, it is believed that viral antigen alone may not be responsible for driving the response. In a number of viral brain infections, it is clear that residnt microglia are activated by brain-infiltrating cells of the peripheral immune system, as well as by their mediators, rather than simply viral antigens themselves. Using a murine cytomegalovirus (MCMV) model of viral brain infection, we were surprised to detect numerous CD19(-)CD38(+)CD138(+) plasma cells and CD19(+)CD1d(high)CD5(+) regulatory B-cells (Breg) persisting in the CNS during chronic infection. Based on these preliminary findings, it is likely that antibodies present within the CNS, operating through Fc receptors, and persisting Breg cells influence neuroimmune activation. In this proposal, the central hypothesis to be tested is that B-lineage cells persisting within the CNS following viral infection modulate chronic microglial cell activation. In the proposed studies, we will first determine whether an environment capable of supporting entry and survival of B-lineage cells (i.e., B-cells, plasma blasts, plasma cells, and Breg cells) is produced following viral brain infection. We will then fin out whether antibody-secreting cell (ASC)-produced antibodies modulate microglial cell activation within the infected brain. This will be achieved by determining how the ratios of activating (i.e., Fc RI, Fc RIII) to inhibitory (i.e., Fc RIIb) Fc receptors on microglia change in response to viral brain infection and by comparing infection-induced microglial cell activation in wild-type versus Fc RI/RIII double-knockout, as well as Fc RIIb knockout animals. We will go on to investigate how regulatory B-cells modulate microglial cell activation through both anti-inflammatory cytokine- and contact-dependent mechanisms. The final set of experiments will use Foxp3 promoter-GFP- and Foxp3-DTR (diphtheria toxin receptor) expressing transgenic animals to investigate how Breg cells promote CD4(+) lymphocyte transition into a T regulatory (Treg) cell phenotype within the chronically infected brain. The interactions between brain-infiltrating cells of the B- lineage, the cytokines and antibodies they produce, and their role in regulating chronic microglial cell activation, which is the focus of this application, have largely been ignored in experimental models of NeuroAIDS. Because B-lineage cells are present in the brain during chronic viral infection, the roles they play in modulating microglial cell activation nd its associated neurodegeneration need to be explored.

Public Health Relevance

Neurological complications of HIV infection continue to increase in prevalence as patients with the disease live longer and cognitive impairment remains one of the most feared complications;even in patients with systemically well-controlled virus. The neurodegenerative consequences of subclinical viral infection and its associated chronic, low-grade neuroimmune activation have not been elucidated. It is clear that microglial cells are activated by immune responses and neuroimmune activation has been shown to persist long after reduction of HIV RNA levels by effective HAART. Without new therapeutic approaches that target microglial activation and thus complement HAART, a burgeoning population of aging HIV-infected patients will face neurocognitive decline that significantly decreases their quality of life.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038836-16
Application #
8608602
Study Section
Special Emphasis Panel (ZRG1-AARR-C (02))
Program Officer
Wong, May
Project Start
2000-01-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
16
Fiscal Year
2014
Total Cost
$342,000
Indirect Cost
$117,000
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Cheeran, Maxim C-J; Mutnal, Manohar B; Hu, Shuxian et al. (2009) Reduced lymphocyte infiltration during cytomegalovirus brain infection of interleukin-10-deficient mice. J Neurovirol 15:334-42

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