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IL-2 therapy leads to dose-dependent, sustained CD4 cell count increases in most HIV-infected patients treated with antiretroviral therapy (ART) [1,2]. Early increases in both CD4+ and CD8+ T cell subsets occurs, but only the CD4+ T cell population maintains higher numbers over the long-term [3,4]. The mechanism may involve the ability of CD4+ T cells to better upregulate the high affinity IL-2 receptor, CD25 or it may involve preferential survival of CD4+ T cells. Recent data suggests that the expansion of CD25 expressing cells after IL-2 administration is associated with less proliferation of T cells in the long-term (12 months) as measured by both Ki67 expression [3,4] and after in vivo labeling of DNA . It is suggested that IL-2 actually allows CD4 expansion to be maintained by decreasing immune activation levels. One possible explanation is that IL-2 causes the expansion of regulatory CD4+ CD25+ T cells, which might limit subsequent CD4 T cell activation .
Other predictors of the amount of CD4 restoration after IL-2 include the CD4 nadir and the age of the patient [6,7]. The lower the CD4 nadir, the fewer numbers of CD4+ T cells return after IL-2 therapy. Likewise, the older the IL-2 treated patient, the less likely they are to respond well to IL-2, especially after three cycles . Non-responders to IL-2 therapy also tend to have more T cell proliferation at baseline, as well as reduced numbers of recent thymic emigrants, suggesting increased turnover of the peripheral T cell pool [6,7].
In another study, a predictor of the amount of CD4+ T cell return after IL-2 therapy was being non-white; this group of individuals had almost a 200 cells/mm3 larger increase in CD4 cell counts than the white group studied from a cohort of more than 250 patients .
Another feature of HIV pathogenesis that might influence T cell normalization after immune reconstitution is the increased cell death of both CD4+ and CD8+ T cells that is commonly seen in HIV-infected patients. Increased CD4+ T cell death could be due to HIV infection directly or bystander CD4+ T cells may die via multiple mechanisms (8–10). CD8+ T cell death is likely due to increased activation [11-13]. In terms of reduction of lymphocytic apoptosis after ART, several studies show a reduction; however, apoptosis levels do not return to normal levels, but remain elevated in most [14-16].
One study showed that the levels of T cell apoptosis, especially CD8+ T cell apoptosis, was associated with recovery of CD4+ T cell numbers after ART, so that higher levels of CD8+ T cell apoptosis was associated with fewer CD4+ T cells after therapy . This is consistent with our own cross-sectional observation that patients with fewer CD4+ T cells also had more CD8+ T cell apoptosis, whether or not they were on ART therapy . Another study has shown that the amount of CD4+ T cell apoptosis was reduced after four weeks with or without IL-2 therapy, but reduction of CD8+ T cell apoptosis levels took 24 weeks to develop . However, levels of lymphocytic apoptosis were still higher than in controls and was similarly elevated in both ART treated and ART plus IL-2 treated patients [19,20]. When lymph nodes were examined for levels of T cell death before and after ART, low levels of CD8+ T cell apoptosis remained after ART, which were reflective of continuing low levels of viral replication .
The present Houston Vanguard sub-study examines a small group of subcutaneously IL-2 (scIL-2) treated patients. Patients were randomized from October 1998 to May 1999. An exploratory analysis of immunologic status was assessed an average of six years after randomization. We found that, in this small group of patients, the level of spontaneous CD8+ T cell apoptosis at baseline before commencing scIL-2 therapy was associated with both CD4 cell counts as well as CD4:CD8 ratio normalization after six years. These differences in T cell numbers based on initial CD8+ T cell apoptosis levels appeared after two years of scIL-2 therapy and were maintained until the current analysis.
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