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Blood, 1 October 2001, Vol. 98, No. 7, pp. 2166-2174
IMMUNOBIOLOGY
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
Eric Guillemard,
Marie-Thérèse Nugeyre,
Laurent Chêne,
Nathalie Schmitt,
Catherine Jacquemot,
Françoise Barré-Sinoussi, and
Nicole Israël
From Unité de Biologie des Rétrovirus,
Institut Pasteur, Paris, France.
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+ CD8CD3 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.
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