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J. Virol. doi:10.1128/JVI.01582-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Single cell, phosphoepitope-specific analysis demonstrates cell type- and pathway-specific dysregulation of Jak/STAT and MAPK signaling associated with in vivo HIV-1 infection

From the Baxter Laboratory of Genetic Pharmacology, Department of Microbiology and Immunology, and the Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA 94305, Division of Experimental Medicine, UCSF Box 1234, San Francisco, CA 94143-1234, Gladstone Institute of Virology and Immunology, UCSF, 1650 Owens Street, San Francisco, CA 94158-2261, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York 10461, and San Mateo County San Francisco AIDS Research Center (PARC), San Mateo County General Hospital and Health Department, San Mateo, CA 94403

	Abstract

Despite extensive evidence of cell signaling alterations induced by HIV-1 in vitro, the relevance of these changes to the clinical and/or immunologic status of HIV-1 infected individuals is often unclear. As such, mapping the details of cell type specific degradation of immune function as a consequence of changes to signaling network responses has not been readily accessible. We employed a flow cytometric-based assay of signaling to determine Jak/STAT signaling changes at the single cell level within distinct cell subsets from the primary immune cells of HIV-1 infected donors. We identified a specific defect in granulocyte macrophage colony stimulating factor (GM-CSF)-driven Stat5 phosphorylation in the monocytes of HIV-1+ donors. This inhibition was statistically significant in a cohort of treated and untreated individuals. Ex vivo Stat5 phosphorylation levels varied among HIV-1+ donors, but did not correlate with CD4+ T cell counts or HIV-1 plasma viral load. Low Stat5 activation occurred in HIV-1 infected donors despite normal GM-CSF receptor levels. Investigation of MAPK pathways, also stimulated by GM-CSF, led to the observation that LPS-stimulated ERK phosphorylation is enhanced in monocytes. Thus, we have identified a specific, imbalanced monocyte signaling profile, with inhibition of STAT and enhancement of MAPK signaling, associated with HIV-1 infection. This understanding of altered monocyte signaling responses that contribute to defective antigen presentation during HIV-1 infection could lead to immunotherapeutic approaches that compensate for the deficiency.