{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:56:36Z","timestamp":1791356196485,"version":"4.3.1"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2011,9,1]],"date-time":"2011-09-01T00:00:00Z","timestamp":1314835200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Recent evidence demonstrates that HIV-1 infection leads to the attenuation of cellular immune responses, which has been correlated with the increased expression of programmed death (PD)-1 on virus-specific CD8+ T cells. PD-1 is induced upon T cell activation, and its prolonged expression facilitates CD8+ T cell inhibitory signals when bound to its B7 family ligands, PD-ligand (L)1\/2, which are expressed on APCs. Importantly, early reports demonstrated that blockade of the PD-1\/PD-L interaction by Abs may help to counter the development of immune exhaustion driven by HIV viral persistence. To better understand the regulation of the PD-1 pathway during HIV infection, we examined the ability of the virus to induce PD-L expression on macrophages and dendritic cells. We found a direct relationship between the infection of APCs and the expression of PD-L1 in which virus-mediated upregulation induced a state of nonresponsiveness in uninfected HIV-specific T cells. Furthermore, this exhaustion phenotype was revitalized by the blockade of PD-L1, after which T cells regained their capacity for proliferation and the secretion of proinflammatory cytokines IFN-\u03b3, IL-2, and IL-12 upon restimulation. In addition, we identify a critical role for the PI3K\/serine\u2013threonine kinase signaling pathway in PD-L1 upregulation of APCs by HIV, because inhibition of these intracellular signal transducer enzymes significantly reduced PD-L1 induction by infection. These data identify a novel mechanism by which HIV exploits the immunosuppressive PD-1 pathway and suggest a new role for virus-infected cells in the local corruption of immune responses required for viral suppression.<\/jats:p>","DOI":"10.4049\/jimmunol.1100594","type":"journal-article","created":{"date-parts":[[2011,8,20]],"date-time":"2011-08-20T02:43:58Z","timestamp":1313808238000},"page":"2932-2943","source":"Crossref","is-referenced-by-count":38,"title":["HIV-Mediated Phosphatidylinositol 3-Kinase\/Serine\u2013Threonine Kinase Activation in APCs Leads to Programmed Death-1 Ligand Upregulation and Suppression of HIV-Specific CD8 T Cells"],"prefix":"10.1093","volume":"187","author":[{"given":"Karuppiah","family":"Muthumani","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devon J","family":"Shedlock","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel K","family":"Choo","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Fagone","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omkar U","family":"Kawalekar","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Goodman","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoran B","family":"Bian","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aarti A","family":"Ramanathan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parikh","family":"Atman","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Tebas","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A","family":"Chattergoon","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, The Johns Hopkins Hospital , Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew Y","family":"Choo","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School , Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B","family":"Weiner","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,9,15]]},"reference":[{"key":"2025032410355082900_r1","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1046\/j.1440-1711.1999.00833.x","article-title":"Interactions of HIV-1 with antigen-presenting cells","volume":"77","author":"Hewson","year":"1999","journal-title":"Immunol. 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