Anti-HIV state but not apoptosis depends on IFN signature in CD4+ T cells.
To gain insights into the molecular mechanisms underlying early host responses to HIV in the CD4(+) T cell target population, we examined gene expression in CD4(+) T cells isolated 24 h after ex vivo HIV infection of lymphocyte aggregate cultures derived from human tonsils. Gene profiling showed a distinct up-regulation of genes related to immune response and response to virus, notably of IFN-stimulated genes (ISGs), irrespective of the coreceptor tropism of the virus. This mostly IFN-alpha-dependent gene signature suggested the involvement of plasmacytoid dendritic cells, a principal component of the antiviral immune response. Indeed, depletion of plasmacytoid dendritic cells before HIV inoculation abrogated transcriptional up-regulation of several ISGs and resulted in increased levels of HIV replication. Treatment with a blocking anti-IFN-alphaR Ab yielded increased HIV replication; conversely, HIV replication was decreased in pDC-depleted cultures treated with IFN-alpha. Among up-regulated ISGs was also TRAIL, indicating a potential role of the IFN signature in apoptosis. However, a blocking anti-TRAIL Ab did not abrogate apoptosis of CD4(+) T cells in CXCR4-tropic HIV-infected cultures, suggesting the involvement of pathways other than TRAIL mediated. We conclude that acute HIV infection of lymphoid tissue results in up-regulation of ISGs in CD4(+) T cells, which induces an anti-HIV state but not apoptosis.
Audigé
Annette
A
Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Zurich, Raemistrasse 100, 8091 Zurich, Switzerland.
Urosevic
Mirjana
M
Schlaepfer
Erika
E
Walker
Russell
R
Powell
Doug
D
Hallenberger
Sabine
S
Joller
Helen
H
Simon
Hans-Uwe
HU
Dummer
Reinhard
R
Speck
Roberto F
RF
D019138:Antibodies, Blocking / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology*; D003713:Dendritic Cells / Q000276:immunology; D020869:Gene Expression Profiling; D006678:HIV / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007109:Immunity / Q000235:genetics; D016898:Interferon-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D007372:Interferons / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014066:Palatine Tonsil / Q000821:virology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors; D015854:Up-Regulation; D014779:Virus Replication / Q000187:drug effects
D019138:Antibodies, Blocking; D016898:Interferon-alpha; D053221:TNF-Related Apoptosis-Inducing Ligand; D007372:Interferons