Background: Interleukin (IL)-7 levels are elevated as a homeostatic response to various T-cell depleting conditions. T-cell depletion in HIV-infected patients (pts) has been correlated with increased IL-7 levels. Furthermore, elevated IL-7 levels have been touted as an indicator of HIV disease progression. Studies presented here investigate T-cell homeostasis and plasma IL-7 levels in the simian immunodeficiency virus (SIV) macaque animal model.

Methods: The levels of plasma IL-7 were assessed in 6 macaques intravenously inoculated with pathogenic SIVmac239. The macaques were assessed longitudinally for the following: viral load, CD4⁺ T-cells, recent thymic emigrants (TREC), naive and memory T-cell subsets, and actively proliferating T-cells (Ki67⁺). Comparisons of these immunologic parameters and plasma IL-7 levels were undertaken utilizing graphical as well as statistical analyses.

Results: We have found that IL-7 levels are elevated in SIVmac239 infected macaques, often at times just prior to simian AIDS and death. A strong correlation (p < 0.05) was observed between increasing plasma IL-7 levels and declining CD4⁺ T-cells (3 of 6 macaques) as well as declining levels of TREC in CD8⁺ T-cells (4 of 6 macaques). A temporal assessment of the events in the SIV infected macaques indicated that a decline in CD4⁺ T-cells and the CD8⁺ TREC containing T-cell subset was followed by an increase in plasma IL-7 levels. In the rhesus macaques that did not progress rapidly to disease, elevated IL-7 levels were then followed by an increase in the proliferation of CD4⁺ and CD8⁺ T-cells (Ki67). In addition, removal of the thymus prior to SIV infection accelerated the onset of IL-7 increase, further implicating the importance of recent thymic emigrants (TREC⁺ cells) in regulation of plasma IL-7 levels.

Conclusions: These findings support a model in which progressive loss of CD4⁺ T-cells and recent thymic emigrants trigger a compensatory IL-7-dependent feedback loop to stimulate both thymic output and post-thymic peripheral T-cell proliferation. However, this compensatory T-cell proliferation may ultimately result in an increased number of T-cells available for SIV infection, thus creating an immune environment that favors SIV/HIV replication and disease progression. These studies provide further evidence that the SIV-macaque model will be useful to assess future therapies to aid recovery of proper T-cell homeostasis in HAART treated HIV-infected pts.