Abstract
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.
Highlights
Introduction crucial cofactor of tumor necrosis factor (TNF) to promote human immunodeficiency virus (HIV) replication, is shown here to counteract the apoptotic activity of TNF
There is no implication of the expression level of the CXCR4 coreceptor used by HIV-1B-LAIp, which is even less expressed in single-positive CD4ϩCD8ϪCD3ϩ (SP CD4ϩ) thymocytes than in immature thymocytes (38,39 and data not shown)
We address whether such a mechanism occurs in mature SP CD4ϩIL-7RhighBcl-2high thymocytes, which might further strengthen their resistance to apoptosis on HIV infection
Summary
Introduction crucial cofactor of tumor necrosis factor (TNF) to promote HIV replication, is shown here to counteract the apoptotic activity of TNF. Intermediate thymocytes, which replicate the virus at a lower level, are more sensitive to apoptosis, and their differentiation into doublepositive 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. Thymuses from pediatric patients who experienced accelerated disease processes[12,13] or from adults with acquired immunodeficiency syndrome (AIDS)[14,15] showed severe thymocyte depletion associated with a profound disorganization of the thymic epithelial network Such alterations correlate with the presence of the virus in the thymuses of humans[16,17,18] and animals, among them infected macaques[19,20] and SCID-hu mice.[21,22]. E.G. was the recipient of a fellowship from Ensemble contre le SIDA (Fondation pour la Recherche Medicale, Paris, France) and a fellowship from the Agence Nationale pour la Recherche sur le SIDA
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
