PMID- 23902750
OWN - NLM
STAT- MEDLINE
DCOM- 20140303
LR  - 20211021
IS  - 1742-2094 (Electronic)
IS  - 1742-2094 (Linking)
VI  - 10
DP  - 2013 Jul 31
TI  - T-cell reconstitution during murine acquired immunodeficiency syndrome (MAIDS) 
      produces neuroinflammation and mortality in animals harboring opportunistic viral 
      brain infection.
PG  - 98
LID - 10.1186/1742-2094-10-98 [doi]
AB  - BACKGROUND: Highly 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. 
      METHODS: Utilizing 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. 
      RESULTS: Infection 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. CONCLUSIONS: Taken 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.
FAU - Mutnal, Manohar B
AU  - Mutnal MB
AD  - Neuroimmunology Laboratory, Center for Infectious Diseases and Microbiology 
      Translational Research, Department of Medicine, University of Minnesota, 3-220 
      LRB/MTRF, 2001 6th Street S.E., Minneapolis, MN 55455, USA.
FAU - Schachtele, Scott J
AU  - Schachtele SJ
FAU - Hu, Shuxian
AU  - Hu S
FAU - Lokensgard, James R
AU  - Lokensgard JR
LA  - eng
GR  - R01 MH066703/MH/NIMH NIH HHS/United States
GR  - MH-066703/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130731
PL  - England
TA  - J Neuroinflammation
JT  - Journal of neuroinflammation
JID - 101222974
SB  - IM
MH  - AIDS-Related Opportunistic Infections/*immunology/mortality/pathology
MH  - Animals
MH  - CD4-Positive T-Lymphocytes/*immunology/pathology/virology
MH  - CD8-Positive T-Lymphocytes/*immunology/pathology/virology
MH  - Central Nervous System Viral Diseases/*immunology/mortality/pathology
MH  - Herpes Simplex/*immunology/mortality/pathology
MH  - Inflammation/immunology/mortality/pathology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Murine Acquired Immunodeficiency Syndrome/*immunology/mortality/pathology
PMC - PMC3735417
EDAT- 2013/08/02 06:00
MHDA- 2014/03/04 06:00
PMCR- 2013/07/31
CRDT- 2013/08/02 06:00
PHST- 2013/05/16 00:00 [received]
PHST- 2013/07/16 00:00 [accepted]
PHST- 2013/08/02 06:00 [entrez]
PHST- 2013/08/02 06:00 [pubmed]
PHST- 2014/03/04 06:00 [medline]
PHST- 2013/07/31 00:00 [pmc-release]
AID - 1742-2094-10-98 [pii]
AID - 10.1186/1742-2094-10-98 [doi]
PST - epublish
SO  - J Neuroinflammation. 2013 Jul 31;10:98. doi: 10.1186/1742-2094-10-98.