IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells

Abstract

Murine models indicate that interleukin-10 (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 up-regulated 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 peripheral blood mononuclear cells (PBMCs), correlated positively with viral load and diminished after successful antiretroviral therapy. IL-10 mRNA levels were up-regulated in multiple PBMC subsets in HIV-infected subjects compared with HIV-negative controls, particularly in T, B, and natural killer (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.

Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4 + T cells, and disease progression

“…We found that vRC was positively correlated with a number of inflammatory cytokines (Table 2), most notably IL-6 and IL-1β, two proinflammatory cytokines previously implicated in driving aberrant CD4 + T-cell turnover and impairing homeostatic proliferation (21). Of note, vRC was also strongly correlated with elevated levels of IL-10, an important antiinflammatory cytokine linked to T-cell dysfunction in HIV infection (22,23).…”

“…Previous studies demonstrated that increased PD-1 expression by monocytes, due to the presence of microbial products and inflammatory cytokines in HIV-1 infection, can lead to the production IL-10, which further disrupts T-cell function (23). Moreover, IL-10 blockade restored the antigen-induced proliferation of HIV-specific CD4 + and CD8 + T cells in vitro, as well as the production of effector cytokines by HIV-specific CD4 + T cells (22). Thus, in the present study, enhanced IL-10 production may reflect a dysregulated innate and adaptive immune response brought on by intensified viral replication during acute infection.…”

Immunological Profiles in HIV Positive Patients with or without Opportunistic Infections and the Influence of Highly Active Antiretroviral Therapy: A Systematic Review and Update

“…With the growing understanding of their roles during infections and disease progression, cytokines including IFN-γ, IL-10 and tumor necrosis factor alpha (TNF-α) have been assayed in plasma to assess the efficacy of antiretroviral therapy during HIV infection [24,25]. For example, HAART markedly increases plasma IFN-γ levels [26,27], and considerably lowers IL-10 systemic levels during HIV infection [25].…”

Transient IL-10 receptor blockade can enhance CD8+T cell responses to a simian adenovirus-vectored HIV-1 conserved region immunogen

“…10,11 Antibody blockade of the IL-10R restored proliferation and cytokine production by HIV-1-specific CD4 C and CD8 C T cells in vitro. 12,13 We investigated whether inhibition of IL-10 signaling at the time of immunization could enhance CD8 C T cell responses to an adenovirus-vectored HIV-1 vaccine candidate, ChAdV63. HIVconsv, which was recently shown to be immunogenic in a phase I clinical trial.…”