{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:05:16Z","timestamp":1790705116621,"version":"4.1.0"},"reference-count":32,"publisher":"American Society for Microbiology","issue":"23","license":[{"start":{"date-parts":[[2017,12,1]],"date-time":"2017-12-01T00:00:00Z","timestamp":1512086400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100003323","name":"Agence Nationale de Recherches sur le Sida et les H\u00e9patites Virales","doi-asserted-by":"publisher","award":["AO2015-2-17046"],"award-info":[{"award-number":["AO2015-2-17046"]}],"id":[{"id":"10.13039\/501100003323","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The neuroimmune dialogue between peripheral neurons and Langerhans cells (LCs) within mucosal epithelia protects against incoming pathogens. LCs rapidly internalize human immunodeficiency virus type 1 (HIV-1) upon its sexual transmission and then\n            <jats:italic>trans<\/jats:italic>\n            -infect CD4\n            <jats:sup>+<\/jats:sup>\n            T cells. We recently found that the neuropeptide calcitonin gene-related peptide (CGRP), secreted mucosally from peripheral neurons, inhibits LC-mediated HIV-1\n            <jats:italic>trans<\/jats:italic>\n            -infection. In this study, we investigated the mechanism of CGRP-induced inhibition, focusing on HIV-1 degradation in LCs and its interplay with\n            <jats:italic>trans<\/jats:italic>\n            -infection. We first show that HIV-1 degradation occurs in endolysosomes in untreated LCs, and functionally blocking such degradation with lysosomotropic agents results in increased\n            <jats:italic>trans<\/jats:italic>\n            -infection. We demonstrate that CGRP acts via its cognate receptor and at a viral postentry step to induce faster HIV-1 degradation, but without affecting the kinetics of endolysosomal degradation. We reveal that unexpectedly, CGRP shifts HIV-1 degradation from endolysosomes toward the proteasome, providing the first evidence for functional HIV-1 proteasomal degradation in LCs. Such efficient proteasomal degradation significantly inhibits the first phase of\n            <jats:italic>trans<\/jats:italic>\n            -infection, and proteasomal, but not endolysosomal, inhibitors abrogate CGRP-induced inhibition. Together, our results establish that CGRP controls the HIV-1 degradation mode in LCs. The presence of endogenous CGRP within innervated mucosal tissues, especially during the sexual response, to which CGRP contributes, suggests that HIV-1 proteasomal degradation predominates\n            <jats:italic>in vivo<\/jats:italic>\n            . Hence, proteasomal, rather than endolysosomal, HIV-1 degradation in LCs should be enhanced clinically to effectively restrict HIV-1\n            <jats:italic>trans<\/jats:italic>\n            -infection.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            During sexual transmission, HIV-1 is internalized and degraded in LCs, the resident antigen-presenting cells in mucosal epithelia. Yet during\n            <jats:italic>trans<\/jats:italic>\n            -infection, infectious virions escaping degradation are transferred to CD4\n            <jats:sup>+<\/jats:sup>\n            T cells, the principal HIV-1 targets. We previously found that the neuroimmune dialogue between LCs and peripheral neurons, innervating mucosal epithelia, significantly inhibits\n            <jats:italic>trans<\/jats:italic>\n            -infection via the action of the secreted neuropeptide CGRP on LCs. In this study, we investigated whether CGRP-induced inhibition of\n            <jats:italic>trans<\/jats:italic>\n            -infection is linked to CGRP-controlled HIV-1 degradation in LCs. We show that in untreated LCs, HIV-1 is functionally degraded in endolysosomes. In sharp contrast, we reveal that in CGRP-treated LCs, HIV-1 is diverted toward and degraded via another cytosolic protein degradative pathway, namely, the proteasome. These results establish that CGRP regulates HIV-1 degradation in LCs. As CGRP contributes to the sexual response and present within mucosal epithelia, HIV-1 proteasomal degradation in LCs might predominate\n            <jats:italic>in vivo<\/jats:italic>\n            and should be enhanced clinically.\n          <\/jats:p>","DOI":"10.1128\/jvi.01205-17","type":"journal-article","created":{"date-parts":[[2017,9,14]],"date-time":"2017-09-14T01:20:52Z","timestamp":1505352052000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":21,"title":["Calcitonin Gene-Related Peptide Induces HIV-1 Proteasomal Degradation in Mucosal Langerhans Cells"],"prefix":"10.1128","volume":"91","author":[{"given":"Morgane","family":"Bomsel","sequence":"first","affiliation":[{"name":"Laboratory of Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, CNRS UMR 8104, Paris, France"},{"name":"INSERM U1016, Paris, France"},{"name":"Paris Descartes University, Sorbonne Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonatan","family":"Ganor","sequence":"additional","affiliation":[{"name":"Laboratory of Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, CNRS UMR 8104, Paris, France"},{"name":"INSERM U1016, Paris, France"},{"name":"Paris Descartes University, Sorbonne Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2010.32"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002100"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2007.01.007"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.1923"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1541"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02472-06"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400630"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2016.05.123"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature20567"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.9.6020"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/363159a0"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20122349"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/apha.12366"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni841"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12977-014-0123-7"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-4141(199909)29:09<2695::AID-IMMU2695>3.0.CO;2-Q"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0809577"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2009.10.014"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.22.11440-11446.2002"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.78.3.1375-1383.2004"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.5.3845-3850.1998"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.9.5705-5712.2005"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.04.008"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0050722"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/313054a0"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5347(17)37989-2"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejogrb.2013.02.012"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05662"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.187.6.961"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V100.2.701"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.2144\/000112624"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-364-6_13"}],"container-title":["Journal 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