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J. Virol. doi:10.1128/JVI.00324-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Diminished Production of Monocyte Proinflammatory Cytokines During HIV Viremia is Mediated by Type I Interferon

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA; Clinical Services Program, SAIC-Frederick Inc., Frederick, Maryland, USA

^* To whom correspondence should be addressed. Email: mconnors{at}niaid.nih.gov.

	Abstract

The effect of HIV infection and high-level HIV replication on the function of monocytes was investigated. HIV-positive patients had elevated spontaneous production of some or all of the monocyte proinflammatory cytokines measured (IL-1, IL-6, and TNF-) compared to uninfected controls. In patients on therapy with high frequencies of monocytes producing proinflammatory cytokines, this frequency was diminished in the context of viremia during an interruption of therapy. Diminished production of proinflammatory cytokines during viremia was restored by culture with autologous CD4⁺ T cells or monocytes from an on therapy time point, or lipopolysaccharide (LPS). Microarray analysis demonstrated that diminished monocyte production of proinflammatory cytokines was correlated with elevated type I interferon-stimulated gene transcripts. Addition of exogenous IFN-2A diminished the spontaneous production of IL-1, IL-6, and TNF- but did not affect responses to LPS, recapitulating the changes observed in HIV viremic patients. These results suggest that during high-level HIV viremia, monocyte function is diminished and that this effect is mediated by chronic stimulation by type I interferons. This effect on monocytes during viremia may play a role in diminished innate or adaptive immune system functions in HIV-infected patients. In addition, restoration of these functions may also play a role in some immune reconstitution syndromes observed during initiation of therapy.

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