Early initiation of ART normalized enhanced Trp catabolism and immune activation but did not improve plasma levels of gut mucosal dysfunction markers.

IL-21 is a relatively newly discovered immune-enhancing cytokine that plays an essential role in controlling chronic viral infections. It is produced mainly by CD4+ T cells, which are also the main targets of HIV-1 and are often depleted in HIV-infected individuals. Therefore, we sought to determine the dynamics of IL-21 production and its potential consequences for the survival of CD4+ T cells and frequencies of HIV-specific CTL. For this purpose, we conducted a series of cross-sectional and longitudinal studies on different groups of HIV-infected patients and show in this study that the cytokine production is compromised early in the course of the infection. The serum cytokine concentrations correlate with CD4+ T cell counts in the infected persons. Among different groups of HIV-infected individuals, only elite controllers maintain normal production of the cytokine. Highly active antiretroviral therapy only partially restores the production of this cytokine. Interestingly, HIV infection of human CD4+ T cells inhibits cytokine production by decreasing the expression of c-Maf in virus-infected cells, not in uninfected bystander cells. We also show that the frequencies of IL-21–producing HIV-specific, but not human CMV-specific, Ag-experienced CD4+ T cells are decreased in HIV-infected viremic patients. Furthermore, we demonstrate in this study that recombinant human IL-21 prevents enhanced spontaneous ex vivo death of CD4+ T cells from HIV-infected patients. Together, our results suggest that serum IL-21 concentrations may serve as a useful biomarker for monitoring HIV disease progression and the cytokine may be considered for immunotherapy in HIV-infected patients.

Human sialidase (neuraminidase) Neu1 catalyzes lysosomal catabolism of sialylated glycoconjugates. Here we show that during the differentiation of monocytes and the monocytic cell line, THP-1, into macrophages, the majority of Neu1 relocalizes from the lysosomes to the cell surface. In contrast to other cellular sialidases Neu2, Neu3, and Neu4, whose expression either remains unchanged or is down-regulated, Neu1 mRNA, protein and activity are specifically increased during the phorbol 12-myristate 13-acetate-induced differentiation, consistent with a significant induction of the transcriptional activity of the Neu1 gene promoter. The lysosomal carboxypeptidase, cathepsin A, which forms a complex with and activates Neu1 in the lysosome, is sorted to the plasma membrane of the differentiating cells similarly to Neu1. Both proteins are first targeted to the lysosome and then are sorted to the LAMP-2-negative, major histocompatibility complex II-positive vesicles, which later merge with the plasma membrane. Similar trafficking was observed for the internalized fluorescent dextran or horseradish peroxidase initially stored in the lysosomal/endosomal compartment. The suppression of Neu1 expression in the THP-1-derived macrophages by small interfering RNA or with anti-Neu1 antibodies significantly reduced the ability of the cells to engulf bacteria or to produce cytokines. Altogether our data suggest that the upregulation of the Neu1 expression is important for the primary function of macrophages and establish the link between Neu1 and the cellular immune response.