The cytokine interleukin-10 (IL-10) is considered immunosuppressive because it is involved in shutting down immune responses. A number of studies have reported that IL-10 levels are increased in the setting of chronic progressive HIV infection. More recently, research has shown that blocking the receptor for IL-10 (IL-10R) can enhance virus-specific immune responses in mice chronically infected with lymphocytic choriomeningitis virus (LCMV).
In a new paper in the journal Blood, Mark Brockman and colleagues from the newly-inaugurated Ragon Institute at Massachussetts General Hospital offer a detailed analysis of IL-10 upregulation in HIV and explore the impact of blocking IL-10R in vitro on HIV-specific CD4 and CD8 T cell responses. The key findings include:
- In vitro blockade of IL-10R significantly increased HIV-specific CD4 and CD8 T cell proliferation, but only in the setting of uncontrolled viremia (there was a positive correlation between viral load and fold-increase in p24-specific proliferation). Blockade had no effect on T cell responses in elite controllers or individuals with undetectable viral loads on antiretroviral therapy (ART). CMV-specific T cell responses were not enhanced overall although blockade did increase these responses in a subset of study participants.
- Plasma levels of IL-10 protein correlated strongly with HIV viral load (R=0.6017; p=0.0001). The same held true for levels of IL-10 messenger RNA (mRNA) measured in peripheral blood mononuclear cells (PBMC). Both measures also correlated positively with the fold-increase in HIV-specific CD4 T cell proliferation obtained with IL-10R blockade in vitro.
- IL-10 mRNA levels were comparable between elite controllers and uninfected controls, but slightly higher among individuals with suppressed viral load on ART.
- Longitudinal analysis of several acutely infected study participants showed that IL-10 levels declined significantly after acute infection resolved; levels were significantly higher when measured within 30 days of infection compared to 6-12 months later.
- An investigation of IL-10 mRNA in different cell subsets revealed that, compared to uninfected controls, levels were significantly higher in CD14+ monocytes, CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD56+ NK cells. There was no significant difference for plasmacytoid dendritic cells and levels were lower in monocyte-derived dendritic cells.
The researchers conclude that while IL-10 is clearly upregulated in HIV infection, its relationship with pathogenesis is likely complex. They cite a prior study suggesting that a genetic polymorphism associated with higher IL-10 production may slow disease progression, and note that this would be consistent with a possible beneficial effect of IL-10 in reducing immune activation (which correlates strongly with HIV disease progression). However, they also point out that a short placebo-controlled trial of IL-10 treatment found no benefit on surrogate markers of disease progression. In terms of the therapeutic potential of IL-10R blockade, the researchers argue that it will likely be limited as they observed no impact on HIV-specific immunity when viral load was controlled by ART. To gain a better understanding of the potential positive and negative effects of IL-10 in HIV, the researchers recommend developing strategies that allow specific targeting of the IL-10 production pathway in different cell subsets.
Blood First Edition Paper, prepublished online April 13, 2009; DOI 10.1182/blood-2008-12-191296.
Mark A. Brockman, Douglas S. Kwon, Daniel P. Tighe, David F. Pavlik, Pamela C. Rosato, Jennifer Sela, Filippos Porichis, Sylvie Le Gall, Michael T. Waring, Kristin Moss, Heiko Jessen, Florencia Pereyra, Daniel G. Kavanagh, Bruce D. Walker, and Daniel E. Kaufmann
Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Charlestown, MA, United States
Harvard Medical School, Boston, MA, United States
Howard Hughes Medical Institute, Chevy Chase, MD, United States
Jessen Praxis, Berlin, Germany
Brigham and Women's Hospital, Boston, MA, United States
Murine models indicate that IL-10 can suppress viral clearance, and interventional blockade of IL-10 activity has been proposed to enhance immunity in chronic viral infections. Increased IL-10 levels have been observed during HIV infection and IL-10 blockade has been shown to enhance T cell function in some HIV-infected subjects. However, the categories of individuals in whom the IL-10 pathway is upregulated are poorly defined, and the cellular sources of IL-10 in these subjects remain to be determined. Here we report that blockade of the IL-10 pathway augmented in vitro proliferative capacity of HIV-specific CD4 and CD8 T cells in individuals with ongoing viral replication. IL-10 blockade also increased cytokine secretion by HIV-specific CD4 T cells. Spontaneous IL-10 expression, measured as either plasma IL-10 protein or IL-10 mRNA in PBMC, correlated positively with viral load and diminished following successful antiretroviral therapy. IL-10 mRNA levels were upregulated in multiple PBMC subsets in HIV infected subjects compared to HIV-negative controls, particularly in T, B, and NK cells, whereas monocytes were a major source of IL-10 mRNA in HIV-infected and uninfected individuals. These data indicate that multiple cell types contribute to IL-10-mediated immune suppression in the presence of uncontrolled HIV viremia.
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