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Although interleukin-10 (IL-10) has been implicated as an important mediator of this T cell dysfunction, the regulation of IL-10 production in chronic HIV-1 infection remains poorly understood. We demonstrated that IL-10 is elevated in the plasma of individuals with chronic HIV-1 infection and that blockade of IL-10 signaling results in a restoration of HIV-1-specific CD4 T cell proliferation, gamma interferon (IFN-\u03b3) secretion, and, to a lesser extent, IL-2 production. Whereas IL-10 blockade leads to restoration of IFN-\u03b3 secretion by HIV-1-specific CD4 T cells in all categories of subjects investigated, significant enhancement of IL-2 production and improved proliferation of CD4 T helper cells are restricted to viremic individuals. In peripheral blood mononuclear cells (PBMCs), this IL-10 is produced primarily by CD14<jats:sup>+<\/jats:sup>monocytes, but its production is tightly controlled by regulatory T cells (Tregs), which produce little IL-10 directly. When Tregs are depleted from PBMCs of viremic individuals, the effect of the IL-10 signaling blockade is abolished and IL-10 production by monocytes decreases, while the production of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-\u03b1), increases. The regulation of IL-10 by Tregs appears to be mediated primarily by contact or paracrine-dependent mechanisms which involve IL-27. This work describes a novel mechanism by which regulatory T cells control IL-10 production and contribute to dysfunctional HIV-1-specific CD4 T cell help in chronic HIV-1 infection and provides a unique mechanistic insight into the role of regulatory T cells in immune exhaustion.<\/jats:p>","DOI":"10.1128\/jvi.06251-11","type":"journal-article","created":{"date-parts":[[2012,4,12]],"date-time":"2012-04-12T05:16:50Z","timestamp":1334207810000},"page":"6586-6594","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":36,"title":["CD4<sup>+<\/sup>CD25<sup>+<\/sup>Regulatory T Cells Impair HIV-1-Specific CD4 T Cell Responses by Upregulating Interleukin-10 Production in Monocytes"],"prefix":"10.1128","volume":"86","author":[{"given":"Douglas S.","family":"Kwon","sequence":"first","affiliation":[{"name":"Ragon Institute of MGH, MIT and Harvard, Charlestown, Massachusetts, USA"},{"name":"Division of Infectious Diseases, 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