Background:  Interleukin (IL)-7 and its signalling via the IL-7 receptor complex is essential for optimal CTL activity. Our demonstration that significantly fewer CD8 cells from HIV-infected patients express CD127 than from healthy individuals, implicates a role for the regulation of CD127 expression in HIV immunopathogenesis. Based on preliminary observations that TNF-a and IL-7 decrease CD127 expression on CD8 cells, we hypothesize that HIV infection alters CD127 expression on CD8 cells and does so by up-regulating production of TNF-a and/or IL-7.

Methods:  Since X4 and R5 strains of HIV appear to have differential effects on TNF-a and IL-7 production, PBMC or isolated CD8 cells from healthy volunteers were incubated with either an X4 (HIV_IIIB), R5 (HIV_BaL), dual tropic (HIV_CS204), or replication incompetent (HIV_8E5) strain of HIV with or without antibodies to TNF-a or IL-7. After various lengths of time (24 to 96 hours), CD127 expression on CD8 cells was evaluated by flow cytometry. CD127 expression on isolated CD8 cells cultured with infected PBMC via a transwell, and isolated CD8 cells cultured with supernatants of PBMC infected with HIV for 24 hours were also studied. The effect of HIV infection on CD127 RNA expression was evaluated by PCR. Infection of PBMC cultures was monitored by p24 ELISA.

Results:  Incubation of PBMC with HIV_IIIB, HIV_BaL, or HIV_CS204 transiently decreased CD127 expression on CD8 cells. However, addition of HIV to isolated CD8 cell cultures had no effect on CD127 expression. HIV_8E5 had no effect on CD127. Isolated CD8 cells exposed to either:  PBMC incubated with HIV_IIIB, HIV_BaL, or HIV_CS204 and cultured in a transwell, or supernatants from HIV incubated with HIV_IIIB, HIV_BaL, or HIV_CS204 resulted in decreased CD127 expression. PCR analysis of RNA isolated from CD8 cells in HIV-infected PBMC demonstrated no change in the levels of CD127 RNA. p24 ELISA confirmed that incubation of PBMC with HIV_IIIB, HIV_BaL, or HIV_CS204 results in productive infection.

Conclusions:  As seen in vivo, HIV infection of PBMC in vitro results in the down-regulation of CD127 surface expression on CD8 cells. This effect appears to be due to the activity of soluble factor(s) present in HIV-infected PBMC cultures. Candidate proteins include TNF-a and IL-7, the roles of which are being evaluated with neutralizing antibody experiments. Further elucidating the mechanism(s) of CD127 down-regulation will provide important insights into the immunopathogenesis of HIV disease.

Keywords: CD127; CD8 T cells; Interleukin-7