Interleukin-7 and infection itself by human immunodeficiency virus 1 favor virus persistence in mature CD4(+)CD8(-)CD3(+) thymocytes through sustained induction of Bcl-2.
The sequence of events and the mechanisms leading to the destruction of the thymus during human immunodeficiency virus (HIV) infection are still poorly characterized. Investigated here are the survival capacity on HIV-1 infection of the mature single-positive CD4(+)CD8(-)CD3(+) (SP CD4(+)) and the intermediate CD4(+) CD8(-)CD3(-) thymocytes previously shown to be able to replicate the virus in the thymic microenvironment. It is demonstrated that the mature SP CD4(+) thymocytes exhibit a high survival capacity despite the production of a high yield of viruses. Interleukin-7, reported to be a crucial cofactor of tumor necrosis factor (TNF) to promote HIV replication, is shown here to counteract the apoptotic activity of TNF. Resistance to apoptosis of SP CD4(+) cells is conferred by a high expression of the IL-7 receptor (IL-7R) associated with the capacity of IL-7 to permanently up-regulate Bcl-2. In addition, this high Bcl-2 level is further enhanced by infection itself. In contrast, intermediate thymocytes, which replicate the virus at a lower level, are more sensitive to apoptosis, and their differentiation into double-positive CD4(+)CD8(+)CD3(-) (DP CD3(-)) cells strongly increases their death rate on infection. This sensitivity is related to a lower expression of IL-7R and Bcl-2 in intermediate thymocytes, which further decreases at the DP CD3(-) stage. In addition, a decreased level of Bcl-2 is observed in this subset during infection. Altogether these data suggest that in vivo, HIV infection might create a persistent virus reservoir within the SP CD4(+) thymocytes, whereas the later infection of intermediate cells might lead to thymopoiesis failure.
Guillemard
E
E
Unité de Biologie des Rétrovirus, Institut Pasteur, Paris, France.
Nugeyre
M T
MT
Chêne
L
L
Schmitt
N
N
Jacquemot
C
C
Barré-Sinoussi
F
F
Israël
N
N
D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis*; D017209:Apoptosis / Q000187:drug effects; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D002470:Cell Survival / Q000187:drug effects; D002675:Child, Preschool; D016207:Cytokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000473:pathology*; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015851:Interleukin-7 / Q000494:pharmacology* / Q000502:physiology; D016131:Lymphocyte Subsets; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D015851:Interleukin-7; D019253:Proto-Oncogene Proteins c-bcl-2; D020395:Receptors, Interleukin-7; D014409:Tumor Necrosis Factor-alpha