Background: There is increasing evidence that HIV-1 specific T-cells are anergic in vivo. The frequencies of HIV-1 specific IFN-g producing CD4⁺ T-cells detected in natural infection are markedly lower when compared to other viral infections, like CMV. HIV-1 specific IFN-g producing CD8⁺ T-cells are demonstrable in all stages of infection despite lack of complete viral supression. The nature of the defect in the HIV-1 specific CD4⁺ and CD8⁺ T-cell immune response is poorly understood. In murine models of anergy, IL-2 has been shown to reverse T-cell anergy. IL-2 is a member of a class of cytokines that binds to receptors containing gc (common gamma chain), and includes IL-4, IL-7, and IL-15.

Objectives: The current study examined the role of gc cytokines in reversing HIV‑1 specific CD4⁺ and CD8⁺ T-cell anergy observed in HIV-1 infection.

Methods: PBMC were obtained ex vivo and cultured overnight with the gc cytokines, IL-2, IL-15, IL-4, or combined IL-15+IL-7, or medium. The following day, the cells were washed and then stimulated by an HIV-1 gag peptide pool for 12 hours and the frequencies of gag specific CD4⁺ T-cells were enumerated by intracellular IFN-g flow cytometry.

Results: Data from 15 HIV‑1 infected individuals with chronic progressive or acute HIV‑1 infection is summarized in the table below:

 

Condition (overnight incubation)	medium	IL-2	IL-15	IL-15+IL-7	IL-4
Mean frequency of gag specific CD4 (% of CD4+ T-cells)	0.08	0.25#	0.55*	0.59*	0.08^
Mean frequency of gag specific CD8 (% of CD8+ T-cells)	0.52	0.96*	1.55*	1.93*	0.48^

* p < 0.05 compared to medium; # p = 0.055 compared to medium; ^ p = n.s. compared to medium

 

Studies, using CFSE as a marker of proliferation, demonstrated that the increased frequencies observed after cytokine exposure were not due to enhanced proliferation of pre-existing antigen specific cells.

Conclusions: These observations support the notion that a significant number of HIV‑1 specific CD4⁺ and CD8⁺ T-cells are circulating in an anergic or unresponsive state, which can be reversed by brief stimulation with the gc cytokines IL-2, IL-15 or IL-15+IL-7. The lack of significant effects with IL-4 suggests that signaling through the common gc alone is not sufficient to reverse anergy, but that signaling through additional receptors like IL-2Rb and IL-15b may also be necessary. The use of IL-2 and particularly IL-15 as an immune modulator to reverse HIV-1 specific CD4⁺ and CD8⁺ T-cell anergy should be investigated.