Background: We have previously shown that exogenous IL-7 can prevent apoptosis and enhance proliferation of immature thymocytes, and also increase CXCR4- (X4) or CCR5- (R5) HIV production in thymic organ culture (TOC). Recent data indicate that plasma IL-7 levels are strongly correlated with T-lymphopenia and viral load and may be associated with emergence of X4-tropic variants in HIV-infected individuals.

Methods: To investigate the regulatory mechanism for IL-7 production after HIV infection, we measured the levels of several cytokines (IL-7, IL-1, tumor necrosis factor [TNF]-a and transforming growth factor [TGF]- in TOC after X4- or R5-tropic HIV-1 infection.  We also measured these cytokines in isolated thymic epithelial cells (TEC) cultured with HIV stimulated or un-stimulated thymocytes.

Results: IL-7 levels in TOC supernatants were significantly increased by infection with X4-tropic, but not R5-tropic, HIV. In X4-tropic HIV-infected TOC, TNF- levels increased rapidly and transiently prior to the increase in IL-7 levels. In contrast, high levels of TNF- lasted more than 3 days in R5-tropic HIV-infected or uninfected TOC. By intracellular TNF- staining on day 3 of TOC, CD3^-CD4^-CD8^- triple negative (TN) cells from X4-tropic HIV-infected TOC showed the highest percentage of TNF- expression (2.77%) compared with uninfected (0.15%) or R5-tropic HIV-infected (0.13%) TOCs. On the other hand, the isolated TEC showed increased IL-7 production in a dose-dependent manner to exogenous TNF-. Furthermore, IL-7 production was significantly enhanced in TEC that were co-cultured with X4-tropic HIV-exposed TN cells but not with control TN cells or by direct HIV exposure.

Conclusions: We demonstrate that IL-7 production is promoted via enhanced production of TNF- by X4 but not R5 HIV-stimulated TN thymocytes. These findings suggest that X4-tropic HIV infection per se may contribute to the elevation of IL-7 levels and thus constitute a positive feedback mechanism for X4-tropic HIV production. Candidate viral antigens involved in this IL-7 production will also be discussed.