This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, A. W.
Right arrow Articles by Nixon, D. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, A. W.
Right arrow Articles by Nixon, D. F.

 Previous Article  |  Next Article 

Journal of Virology, April 2008, p. 3702-3712, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.01582-07
Copyright © 2008, American Society for Microbiology. 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 Human Immunodeficiency Virus Type 1 Infection{triangledown}

Andrew W. Lee,1,2,{ddagger} Elizabeth R. Sharp,3 Alison O'Mahony,4 Michael G. Rosenberg,5 Dennis M. Israelski,2,6 Garry P. Nolan,1,{dagger} and Douglas F. Nixon3*,{dagger}

Baxter Laboratory of Genetic Pharmacology, Department of Microbiology and Immunology,1 Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California 94305,2 Division of Experimental Medicine, UCSF Box 1234, San Francisco, California 94143-1234,3 Gladstone Institute of Virology and Immunology, University of California at San Francisco, 1650 Owens Street, San Francisco, CA 94158-2261,4 Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York 10461,5 San Mateo County San Francisco AIDS Research Center (PARC), San Mateo County General Hospital and Health Department, San Mateo, California 944036

Received 19 July 2007/ Accepted 8 January 2008

Despite extensive evidence of cell signaling alterations induced by human immunodeficiency virus type 1 (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 used a flow cytometric-based assay of signaling to determine Janus kinase/signal transducers and activators of transcription (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 mitogen-activated protein kinase (MAPK) pathways, also stimulated by GM-CSF, led to the observation that lipopolysaccharide-stimulated extracellular signal-regulated kinase 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.

* Corresponding author. Mailing address: Division of Experimental Medicine, University of California at San Francisco, 1001 Potrero Ave., Bldg. 3, UCSF Box 1234, San Francisco, CA 94143-1234. Phone: (415) 206-5518. Fax: (415) 206-5581. E-mail: douglas.nixon{at}ucsf.edu

{triangledown} Published ahead of print on 23 January 2008.

{ddagger} Present address: Merck Research Laboratories, Infectious Diseases/Vaccines Clinical Research, 351 Sumneytown Pike, North Wales, PA 19454.

{dagger} G.P.N. and D.F.N. contributed equally to this study.

Journal of Virology, April 2008, p. 3702-3712, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.01582-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Fleisher, T. A., Oliveira, J. B. (2009). Functional Flow Cytometry Testing: An Emerging Approach for the Evaluation of Genetic Disease. Clin. Chem. 55: 389-390 [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»