Interferon-alpha administration enhances CD8+ T cell activation in HIV infection

Abstract

Background: Type I interferons play important roles in innate immune defense. In HIV infection, type I interferons may delay disease progression by inhibiting viral replication while at the same time accelerating disease progression by contributing to chronic immune activation.

Methods: To investigate the effects of type I interferons in HIV-infection, we obtained cryopreserved peripheral blood mononuclear cell samples from 10 subjects who participated in AIDS Clinical Trials Group Study 5192, a trial investigating the activity of systemic administration of IFNα for twelve weeks to patients with untreated HIV infection. Using flow cytometry, we examined changes in cell cycle status and expression of activation antigens by circulating T cells and their maturation subsets before, during and after IFNα treatment.

Results: The proportion of CD38+HLA-DR+CD8+ T cells increased from a mean of 11.7% at baseline to 24.1% after twelve weeks of interferon treatment (p = 0.006). These frequencies dropped to an average of 20.1% six weeks after the end of treatment. In contrast to CD8+ T cells, the frequencies of activated CD4+ T cells did not change with administration of type I interferon (mean percentage of CD38+DR+ cells = 2.62% at baseline and 2.17% after 12 weeks of interferon therapy). As plasma HIV levels fell with interferon therapy, this was correlated with a "paradoxical" increase in CD8+ T cell activation (p<0.001).

Conclusion: Administration of type I interferon increased expression of the activation markers CD38 and HLA DR on CD8+ T cells but not on CD4+ T cells of HIV+ persons. These observations suggest that type I interferons may contribute to the high levels of CD8+ T cell activation that occur during HIV infection.

Figure 1. CD4+ and CD8+ T cell counts.

The CD4 Cell Count (A) and the CD8 Cell Count (B) are portrayed over the course of interferon-alpha treatment during the ACTG 5192 Study. Week 0 corresponds to the patients' baseline cell counts before beginning Interferon-Alpha Therapy. Weeks 3 and 12 correspond to 3 weeks and 12 weeks of interferon-alpha Therapy. Interferon-Alpha therapy was stopped at Week 12, and therefore Week 18 corresponds to 6 weeks off therapy.

Figure 2. Co-expression of CD38 and HLA-DR on CD4+ and CD8+ T cells.

The percentage of CD4+ T cells (A) and CD8+ T cells (B) co-expressing CD38 and HLA-DR is shown over the course of interferon-alpha treatment during the ACTG 5192 Study. Week 0 corresponds to the patients' baseline cell counts before beginning Interferon-Alpha Therapy. Weeks 3 and 12 correspond to 3 weeks and 12 weeks of interferon-alpha Therapy. Interferon-Alpha therapy was stopped at Week 12, and therefore Week 18 corresponds to 6 weeks off therapy. The bar represents the median value.

Figure 3. Cell cycle status of CD4+ T cells.

The cell cycle status of CD4+ T cells as measured by Ki-67 expression is shown over the course of interferon-alpha treatment during the ACTG 5192 Study. Week 0 corresponds to the patients' baseline cell counts before beginning Interferon-Alpha Therapy. Weeks 3 and 12 correspond to 3 weeks and 12 weeks of interferon-alpha Therapy. Interferon-Alpha therapy was stopped at Week 12, and therefore Week 18 corresponds to 6 weeks off therapy. The bar represents the median value.

Figure 4. Cell cycle status of CD4+ T cell maturation subsets.

The cell cycle status of CD4+ T cell maturation subsets, Central Memory CD4 +T Cells (A), Naive CD4+ T cells (B), Transitional Memory CD4+ T cells (C), and Effector Memory CD4+ Tcells (D), is shown over the course of interferon-alpha treatment during the ACTG 5192 Study. Central memory cells were defined as CD 27+CD45RA− and CCR7+, whereas naïve cells are CD27+, CD45RA+, and CCR7+, transitional memory cells are CD27+, CD45RA−, and CCR7−, and effector memory cells are CD27−, CD45RA−, and CCR7−. Week 0 corresponds to the patients' baseline cell counts before beginning Interferon-Alpha Therapy. Weeks 3 and 12 correspond to 3 weeks and 12 weeks of interferon-alpha therapy. Interferon-Alpha therapy was stopped at Week 12, and therefore Week 18 corresponds to 6 weeks off therapy. The bar represents the median value.