Positive Regulation of CXCR4 Expression and Signaling by Interleukin-7 in CD4⁺Mature Thymocytes Correlates with Their Capacity To Favor Human Immunodeficiency X4 Virus Replication

Abstract

The emergence of X4 human immunodeficiency virus type 1 (HIV-1) variants in infected individuals is associated with poor prognosis. One of the possible causes of this emergence might be the selection of X4 variants in some specific tissue compartment. We demonstrate that the thymic microenvironment favors the replication of X4 variants by positively modulating the expression and signaling of CXCR4 in mature CD4 ؉ CD8؊ CD3 ؉ thymocytes. Here, we show that the interaction of thymic epithelial cells (TEC) with these thymocytes in culture induces an upregulation of CXCR4 expression. The cytokine secreted by TEC, interleukin-7 (IL-7), increases cell surface expression of CXCR4 and efficiently overcomes the downregulation induced by SDF-1␣, also produced by TEC. IL-7 also potentiates CXCR4 signaling, leading to actin polymerization, a process necessary for virus entry. In contrast, in intermediate CD4 ؉ CD8 ؊ CD3 ؊ thymocytes, the other subpopulation known to allow virus replication, TEC or IL-7 has little or no effect on CXCR4 expression and signaling. CCR5 is expressed at similarly low levels in the two thymocyte subpopulations, and neither its expression nor its signaling was modified by the cytokines tested. This positive regulation of CXCR4 by IL-7 in mature CD4؉ thymocytes correlates with their high capacity to favor X4 virus replication compared with intermediate thymocytes or peripheral blood mononuclear cells. Indeed, we observed an enrichment of X4 viruses after replication in thymocytes initially infected with a mixture of X4 (NL4-3) and R5 (NLAD8) HIV strains and after the emergence of X4 variants from an R5 primary isolate during culture in mature thymocytes.

In Vivo Administration of the Recombinant IL-7/Hepatocyte Growth Factor β Hybrid Cytokine Efficiently Restores Thymopoiesis and Naive T Cell Generation in Lethally Irradiated Mice after Syngeneic Bone Marrow Transplantation

“…Alternatively, it is possible that rIL-7/HGFb acts indirectly on ETPs by increasing the generation of their precursors in the BM and/or by supporting the migration of these precursors to the thymus. This possibility is supported by our observations (8) (L. Lai and I. Goldschneider, unpublished observations) that rIL-7/HGFb markedly enhances hematopoiesis and the generation of common lymphoid progenitors and by reports that rIL-7 and rHGF upregulate chemokine receptors and adhesion molecules on a variety of lymphohemopoietic cells (46)(47)(48)(49)(50). It can similarly be speculated that the effect of rIL-7/HGFb on DP thymocytes is secondary to its stimulation of DN thymocytes.…”

Uncoupled Anti-HIV and Immune-Enhancing Effects when Combining IFN-α and IL-7

“…This result contrasts with other studies that describe down-regulation of CXCR4 and CCR5 by IFN-␣ in PBMCs or cell lines and macrophages derived from CD34 ϩ cells from umbilical cord blood, respectively (69,70). Conversely, IL-7 up-regulated CXCR4 expression in T cells, PBMCs, and thymocytes, and this effect was associated with increased susceptibility to infection with X4 HIV strains (28,30,32,37). The disparate results from these and our experiments may be explained by the different experimental systems used.…”

“…Pharmacological doses induce a central renewal and a peripheral expansion of CD4 ϩ and CD8 ϩ T cells in macaques infected with SIV (23,24). However, in vitro, IL-7 enhances HIV replication (2,3,(25)(26)(27)(28)(29)(30)(31)(32). Its effects on HIV replication in SCID-hu mice or SIV-infected monkeys have been inconsistent (23,24,33,34), and IL- 7 has not yet been tested in clinical trials of HIV therapy.…”

Enhanced T cell recovery in HIV-1–infected adults through IL-7 treatment

“…No modifications of antiretroviral regimen or compliance issues with antiretroviral drugs were reported in these patients. Recent in vitro studies have shown that IL-7 may increase HIV infectivity of CD4 + T cells (34)(35)(36). With this in mind, we evaluated the cellular content of viral DNA at entry, at 21 d, and at 12 wk.…”