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In this article, we show that activation of human primary T cells suppresses the early stages of HIV-1 replication in human primary M\u03d5 by downregulating the main cellular receptor for the virus CD4. The secreted factors responsible for this effect have a molecular mass greater than conventional cytokines, are independent of Th1 or Th2 polarization, and are not IFN-\u03b3, IL-16, RANTES, or macrophage inhibitory factor, as revealed by cytokine array analysis and neutralization assays. CD4 downregulation is entirely posttranslational and involves serine phosphorylation of CD4 and its targeting to an intracellular compartment destined for acidification and degradation. CD4 downregulation is dependent on the activities of both protein kinase C and NF-\u03baB as well as the proteasomes. Using high-resolution liquid chromatography-tandem mass spectrometry analysis in conjugation with label-free protein quantitation software, we found that proteins that promote M\u03d5 adherence and spreading, such as attractin, fibronectin, and galectin-3\u2013binding protein, were significantly overrepresented in the activated T cell supernatant fractions. These results reveal the existence of previously unreported anti\u2013HIV-1 proteins, released by activated T cells that downregulate CD4 expression, and are of fundamental importance to understand the kinetics of HIV infection in vivo.<\/jats:p>","DOI":"10.4049\/jimmunol.1003678","type":"journal-article","created":{"date-parts":[[2011,6,11]],"date-time":"2011-06-11T04:01:57Z","timestamp":1307764917000},"page":"748-759","source":"Crossref","is-referenced-by-count":13,"title":["Protein Kinase C and NF-\u03baB\u2013Dependent CD4 Downregulation in Macrophages Induced by T Cell-Derived Soluble Factors: Consequences for HIV-1 Infection"],"prefix":"10.1093","volume":"187","author":[{"given":"Rui Andr\u00e9 Saraiva","family":"Raposo","sequence":"first","affiliation":[{"name":"Sir William Dunn School of Pathology, University of Oxford , Oxford OX1 3RE ,","place":["United Kingdom"]},{"name":"Graduate Program in Areas of Basic and Applied Biology, University of Porto , Porto 4200-465 ,","place":["Portugal"]}]},{"given":"David C","family":"Trudgian","sequence":"additional","affiliation":[{"name":"Sir William Dunn School of Pathology, University of Oxford , Oxford OX1 3RE ,","place":["United Kingdom"]},{"name":"Central Proteomics Facility, Sir William Dunn School of Pathology, University of Oxford , Oxford OX1 3RE ,","place":["United Kingdom"]}]},{"given":"Benjamin","family":"Thomas","sequence":"additional","affiliation":[{"name":"Sir William Dunn School of Pathology, University of Oxford , Oxford OX1 3RE ,","place":["United Kingdom"]},{"name":"Central Proteomics Facility, Sir William Dunn School of Pathology, University of Oxford , Oxford OX1 3RE ,","place":["United Kingdom"]}]},{"given":"Bonnie","family":"van Wilgenburg","sequence":"additional","affiliation":[{"name":"Sir William Dunn School of Pathology, University of Oxford , Oxford OX1 3RE ,","place":["United Kingdom"]}]},{"given":"Sally A","family":"Cowley","sequence":"additional","affiliation":[{"name":"Sir William Dunn School of Pathology, University of Oxford , Oxford OX1 3RE ,","place":["United Kingdom"]}]},{"given":"William","family":"James","sequence":"additional","affiliation":[{"name":"Sir William Dunn School of Pathology, University of Oxford , Oxford OX1 3RE ,","place":["United Kingdom"]}]}],"member":"286","published-online":{"date-parts":[[2011,7,15]]},"reference":[{"key":"2025032410223358100_r1","doi-asserted-by":"crossref","first-page":"4468","DOI":"10.1128\/jvi.64.9.4468-4476.1990","article-title":"Macrophage-tropic strains of human immunodeficiency virus type 1 utilize the CD4 receptor","volume":"64","author":"Collman","year":"1990","journal-title":"J. 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