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Similarly, simian lentiviruses vary in their pathogenicity based on characteristics of both the host species and the virus strain, yet the immune underpinnings that drive differential\n                      <jats:italic>Lentivirus<\/jats:italic>\n                      pathogenicity remain incompletely understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We profile immune responses in a unique model of differential lentiviral pathogenicity where pig-tailed macaques are infected with highly genetically similar variants of SIV that differ in virulence. We apply longitudinal single-cell transcriptomics to this cohort, along with single-cell resolution cell-cell communication techniques, to understand the immune mechanisms underlying lentiviral pathogenicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared to a minimally pathogenic lentiviral variant, infection with a highly pathogenic variant results in a more delayed, broad, and sustained activation of inflammatory pathways, including an extensive global interferon signature. Conversely, individual cells infected with highly pathogenic\n                      <jats:italic>Lentivirus<\/jats:italic>\n                      upregulated fewer interferon-stimulated genes at a lower magnitude, indicating that highly pathogenic\n                      <jats:italic>Lentivirus<\/jats:italic>\n                      has evolved to partially escape from interferon responses. Further, we identify\n                      <jats:italic>CXCL10<\/jats:italic>\n                      and\n                      <jats:italic>CXCL16<\/jats:italic>\n                      as important molecular drivers of inflammatory pathways specifically in response to highly pathogenic\n                      <jats:italic>Lentivirus<\/jats:italic>\n                      infection. Immune responses to highly pathogenic\n                      <jats:italic>Lentivirus<\/jats:italic>\n                      infection are characterized by amplifying regulatory circuits of pro-inflammatory cytokines with dense longitudinal connectivity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our work presents a model of lentiviral pathogenicity where failures in early viral control mechanisms lead to delayed, sustained, and amplifying pro-inflammatory circuits, which in turn drives disease progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13073-024-01290-y","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T07:03:39Z","timestamp":1707116619000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pro-inflammatory feedback loops define immune responses to pathogenic Lentivirus infection"],"prefix":"10.1186","volume":"16","author":[{"given":"Aaron J.","family":"Wilk","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua O.","family":"Marceau","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel W.","family":"Kazer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ira","family":"Fleming","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincent N.","family":"Miao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennyfer","family":"Galvez-Reyes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason T.","family":"Kimata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex K.","family":"Shalek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Holmes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie","family":"Overbaugh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6946-7627","authenticated-orcid":false,"given":"Catherine A.","family":"Blish","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,2,5]]},"reference":[{"key":"1290_CR1","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1086\/314660","volume":"179","author":"JV Giorgi","year":"1999","unstructured":"Giorgi JV, Hultin LE, McKeating JA, Johnson TD, Owens B, Jacobson LP, et al. 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No additional animal work was performed in this study. Our use of these samples was reviewed and approved by Stanford University\u2019s Animal Care and Use Committee as APLAC-33350. This research conforms to the principles of the Helsinki Declaration.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"A. K. S. reports compensation for consulting and\/or SAB membership from Merck, Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Ochre Bio, Third Rock Ventures, Hovione, Relation Therapeutics, FL82, FL86, Bio-Rad Laboratories, Empress Therapeutics, IntrECate Biotherapeutics, Senda Biosciences, and Dahlia Biosciences unrelated to this work. C. A. B. reports compensation for consulting and\/or SAB membership from Catamaran Bio, DeepCell Inc., Immunebridge, and Revelation Biosciences. J. O. reports SAB membership for Aerium Therapeutics. V. N. M. reports compensation from MPM Capital unrelated to this work. S. W. K. reports compensation for consulting from Radera Biotherapeutics and Monopteros Therapeutics. All other authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"24"}}