Effects of interleukin-2 on IL-2, IL-18, RANTES and MIP-1alpha mRNA productions in HIV infected patients

Abstract

HIV infection results in a profound disturbance of immune function, characterised by the reduction of the in vitro production of IL-2; on the contrary, chemokine production is usually increased. IL-2 has been chosen for in vivo immunotherapy and shown a significant recovery of CD4+ T lymphocytes without increasing viral load. Little data on the effects of IL-2 administration in HIV-infected patients on the cytokine and chemokine production. This study was to investigate the effects of IL-2 given subcutaneously on IL-2, IL-18, RANTES and MIP-1alpha mRNA production in PBMC from the IL-2 treated HIV-infected patients. Forty eight HIV-infected patients with CD4 cell counts > 350 cells/mm3 and no history of opportunistic infections were recruited. Patients were randomly assigned to receive either antiretrovirals alone; ddI and d4T (ART) or antiretrovirals plus sc. IL-2 (ART+IL-2) at one of three doses i.e., 1.5, 4.5 and 7.5 MIU bid, every every 12 hours for five days per each cycle. The cycle were repeated in 8 weeks interval for a total of 3 cycles. IL-2, IL-18, RANTES and MIP-1alpha mRNA production were evaluated from PBMC of 10 patients at baseline and week 8 in ART group and at the third cycle (precycle 3, day 4, and day 29) of IL-2 administration in ART+IL-2 group. PBMC collected at baseline and week 16 in both groups were analysed to compare the IL-2 treatment on IL-2 gene expression. And to assess those effect in a dose response, PBMC collected from all of ART plus IL-2 at baseline and day 4 of cycle 1 were analysed. The analysis demonstrated that the proportion of patients with IL-2 mRNA expression in PBMC was significantly higher in the ART plus IL-2 group than those of the ART group (50% vs 0%, P = 0.03) at week 16. The percentages of IL-2 mRNA expression also increased in a dose-response fashion to the IL-2 dosage, i.e., 12.5%, 71% and 77% in 1.5, 4.5 and 7.5 MIU bid, respectively. There were no significant differences in the proportion of patients with IL-18, RANTES, MIP-1alpha and IL-2 mRNA production between baseline and week 8 in the ART group and at precycle 3, day 4, and day 29 in the ART+IL-2 group. These results showed a significant increase in the proportion of patients with IL-2 mRNA expression which was a dose-dependent fashion. In contrast, sc. IL-2 showed no effect on IL-18, RANTES and MIP-1alpha mRNA production. However, a quantitative RT-PCR should be used for future study to quantitatively compare the difference if there was existing. Our findings suggest that a dose of at least 4.5 MIU bid of IL-2 given for 5 days per cycle for a minimum of 2 cycles is effective in enhancing endogenous IL-2 production. Consequently, this may translate into quantitative and qualitative restoration of the immune system