Background:  Previous studies have shown that HIV-infected patients exhibit accelerated T-cell turnover; however little is known about the relationship between lymphocyte cell division and cytokine receptor expression in HIV-infected patients. We sought to determine cytokine receptor expression and cell division responses to a-CD3 stimulation in lymphocytes of HIV-infected children. 

Methods:  The study cohort consisted of 13 pediatric patients with chronic HIV infection differing in viral load (100 to 99,000 mRNA copies/mL) and CD4 counts (0 to 49%). Lymphocytes labeled with CFSE dye (carboxy-fluorescein diacetate, succinimidyl ester) were cultured for 120 hours with either a-CD3 (0.03 mg/mL), IL-2 or IL-15 (both, 100 ng/mL) and cell division was assessed using flow cytometry. Expression of IL2Ra, IL-2Rb, IL-2Rg, IL-7Ra, and IL-15Rawas assessed at baseline. 

Results:  Patients with ongoing viral replication (>10,000 copies/mL, n = 3) and failure of immune reconstitution (CD4 <25%) failed to manifest anti-CD3 induced cell division in CD4 or CD8 T cells. Among immunologic responders (CD4 >25%, n = 7), plasma virus load was <400 copies/mL in 5 and <10,000 copies in 2 patients. Anti-CD3 induced cell division was observed in CD8 T cells (8 to 28 %, median 21%) in the majority (6 of 7) of patients, and in CD4 T cells (5 to 33 %, median 14%) of all except one with the highest virus load (6800 copies/mL). In 4 patients tested, cytokine receptors for IL15a were markedly reduced or absent in CD8 T cells (0 to 6%) as compared with normal controls (mean = 42.7%). IL-2Rg was also reduced in CD4 and CD8 T cells (<25% in both) as compared to controls (mean = 82% and 87%). To evaluate homeostatic proliferation, the response of cells to exogenous IL-2 and IL-15 was evaluated in 3 patients with CD4 >25%. Cell division was noted to occur only in CD8 T cells in response to IL-2 (7 to 24% dividing cells) and in response to IL-15 (10 to 30% dividing cells).

Conclusions:  Anti-CD3 induced cell division is absent in patients with immunologic and virologic failure. Patients with immune reconstitution can manifest anti-CD3-induced cell division responses in both, CD4 and CD8 T cells, but cytokines IL2 and IL-15 induce homeostatic proliferation only in CD8 T cells. Studies of cell division and cytokine receptor expression in CD4 and CD8 T-cell subpopulations might be of critical importance in designing cytokine therapies used alone or as vaccine adjuvants in HIV-infected patients.

Keywords: immune response; cytokines; CD4 and CD8 T cells