Interleukin-7 and infection itself by human immunodeficiency virus 1 favorvirus 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 poorl y characterized. Investigated here are the survival capacity on HIV-1 Infec tion of the mature single-positive CD4(+)CD8(-)CD3(+) (SP CD4(+)) and the i ntermediate CD4(+) CD8(-)CD3(-) thymocytes previously shown to be able to r eplicate the virus in the thymic microenvironment. It is demonstrated that the mature SP CD4(+) thymocytes exhibit a high survival capacity despite th e production of a high yield of viruses. Interleukin-7, reported to be a cr ucial cofactor of tumor necrosis factor (TNF) to promote HIV replication, i s shown here to counteract the apoptotic activity of TNF. Resistance to apo ptosis of SP CD4(+) cells is conferred by a high expression of the IL-7 rec eptor (IL-7R) associated with the capacity of IL-7 to permanently up-regula te Bcl-2. In addition, this high Bcl-2 level is further enhanced by infecti on Itself. In contrast, intermediate thymocytes, which replicate the virus at a lower level, are more sensitive to apoptosis, and their differentiatio n into double-positive CD4(+)CD8(+)CD3(-) (DP CD3(-)) cells strongly increa ses their death rate on infection. This sensitivity is related to a lower e xpression of IL-7R and Bcl-2 in intermediate thymocytes, which further decr eases at the DIP CD3(-) stage. In addition, a decreased level of Bcl-2 is o bserved in this subset during infection. Altogether these data suggest that in vivo, HIV infection might create a persistent virus reservoir within th e SP CD4(+) thymocytes, whereas the later infection of Intermediate cells m ight lead to thymopoiesis failure. (C) 2001 by The American Society of Hema tology.