Generalized immune activation as a direct result of activated CD4+ T cell killing.
BACKGROUND
In addition to progressive CD4(+) T cell immune deficiency, HIV infection is characterized by generalized immune activation, thought to arise from increased microbial exposure resulting from diminishing immunity.


RESULTS
Here we report that, in a virus-free mouse model, conditional ablation of activated CD4(+) T cells, the targets of immunodeficiency viruses, accelerates their turnover and produces CD4(+) T cell immune deficiency. More importantly, activated CD4(+) T cell killing also results in generalized immune activation, which is attributable to regulatory CD4(+) T cell insufficiency and preventable by regulatory CD4(+) T cell reconstitution. Immune activation in this model develops independently of microbial exposure. Furthermore, microbial translocation in mice with conditional disruption of intestinal epithelial integrity affects myeloid but not T cell homeostasis.


CONCLUSIONS
Although neither ablation of activated CD4(+) T cells nor disruption of intestinal epithelial integrity in mice fully reproduces every aspect of HIV-associated immune dysfunction in humans, ablation of activated CD4(+) T cells, but not disruption of intestinal epithelial integrity, approximates the two key immune alterations in HIV infection: CD4(+) T cell immune deficiency and generalized immune activation. We therefore propose activated CD4(+) T cell killing as a common etiology for both immune deficiency and activation in HIV infection.
Marques
Rute
R
Division of Immunoregulation, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
Williams
Adam
A
Eksmond
Urszula
U
Wullaert
Andy
A
Killeen
Nigel
N
Pasparakis
Manolis
M
Kioussis
Dimitris
D
Kassiotis
George
G
D000209:Acute-Phase Proteins; D000818:Animals; D017209:Apoptosis; D018988:Bacterial Translocation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000097:blood; D004195:Disease Models, Animal; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D006706:Homeostasis / Q000276:immunology; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D000099231:Lipopolysaccharide-Binding Protein