{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T04:43:03Z","timestamp":1786164183338,"version":"build-2736575974"},"reference-count":23,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Prevention and Control of Emerging and Major Infectious Diseases\u2014National Science and Technology Major Project","award":["2025ZD01904400"],"award-info":[{"award-number":["2025ZD01904400"]}]},{"name":"Prevention and Control of Emerging and Major Infectious Diseases\u2014National Science and Technology Major Project","award":["2025ZD01900700"],"award-info":[{"award-number":["2025ZD01900700"]}]},{"name":"Prevention and Control of Emerging and Major Infectious Diseases\u2014National Science and Technology Major Project","award":["2026ZD01911700"],"award-info":[{"award-number":["2026ZD01911700"]}]},{"DOI":"10.13039\/501100012166","name":"National Key R & D Program of China","doi-asserted-by":"crossref","award":["2023YFC2306700"],"award-info":[{"award-number":["2023YFC2306700"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Gut-associated lymph nodes (GALNs) constitute an important anatomical reservoir during early and chronic human immunodeficiency virus (HIV)\/simian immunodeficiency virus (SIV) infection, but the fate of this compartment during terminal AIDS remains unclear. This study investigated viral persistence and lymph node injury in a rhesus macaque with long-term SIVmac239 infection and end-stage AIDS, characterized by profound CD4+ T cell depletion (30 cells\/\u03bcL) and persistent viremia (1192 copies\/mL). At necropsy, GALNs, including mesenteric, paracolic, and ileocecal lymph nodes, and non-gut-associated lymph nodes (NGALNs), including hepatic hilar, common iliac, and inguinal lymph nodes, were collected for viral RNA\/DNA quantification, histopathology, immunofluorescence, and transcriptomics. SIV DNA was markedly lower in GALNs than in NGALNs, whereas SIV RNA was detectable only in NGALNs. GALNs exhibited extensive fibrotic remodeling, paracortical collapse, severe CD4+ T cell loss across B cell and paracortical regions, and pronounced CD8+ T cell accumulation within B cell zones. Transcriptomic profiling further revealed an exhaustion signature in GALNs, with reduced DNA replication and repair, impaired cell-cycle activity, and suppressed RNA processing, accompanied by activation of innate immune programs and attenuation of adaptive immune responses. These findings indicate that, during terminal AIDS, GALNs no longer serve as the predominant viral reservoir but instead undergo preferential and severe structural and functional exhaustion. This case highlights marked anatomical heterogeneity in lymph node vulnerability during advanced disease and supports a model in which collapse of the gut-associated immune barrier contributes to disease progression toward terminal AIDS.<\/jats:p>","DOI":"10.3390\/v18080855","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T15:08:09Z","timestamp":1785856089000},"page":"855","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Preferential Exhaustion and Loss of Predominant Reservoir in Gut-Associated Lymph Nodes of a SIVmac239-Infected Rhesus Macaque with Terminal AIDS"],"prefix":"10.3390","volume":"18","author":[{"given":"Cong-Jiao","family":"Bai","sequence":"first","affiliation":[{"name":"College of Life Sciences, Anhui Normal University, Wuhu 241000, China"},{"name":"State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, National Resource Center for Non-Human Primates, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, National Resource Center for Non-Human Primates, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China"},{"name":"School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhang-Ran","family":"Du","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, National Resource Center for Non-Human Primates, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Qiu","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, National Resource Center for Non-Human Primates, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Xue","family":"Sun","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Anhui Normal University, Wuhu 241000, China"},{"name":"State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, National Resource Center for Non-Human Primates, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu-Meng","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, National Resource Center for Non-Human Primates, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5469-0324","authenticated-orcid":false,"given":"Yong-Tang","family":"Zheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, National Resource Center for Non-Human Primates, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China"},{"name":"School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-Zhang","family":"Song","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Anhui Normal University, Wuhu 241000, China"},{"name":"State Key Laboratory of Genetic Evolution & Animal Models, Key Laboratory of Bioactive Peptides of Yunnan Province, National Resource Center for Non-Human Primates, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/imr.12070","article-title":"Pathobiology of HIV\/SIV-associated changes in secondary lymphoid tissues","volume":"254","author":"Estes","year":"2013","journal-title":"Immunol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Lau, J.S.Y., Lewin, S.R., and Telwatte, S. (2025). HIV and the gut: Implications for HIV persistence, immune dysfunction and cure strategies. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1650852"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Siddiqui, S., Perez, S., Gao, Y., Doyle-Meyers, L., Foley, B.T., Li, Q., and Ling, B. (2019). Persistent viral reservoirs in lymphoid tissues in SIV-infected rhesus macaques of Chinese-origin on suppressive antiretroviral therapy. Viruses, 11.","DOI":"10.3390\/v11020105"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/s41385-019-0221-x","article-title":"Despite early antiretroviral therapy effector memory and follicular helper CD4 T cells are major reservoirs in visceral lymphoid tissues of SIV-infected macaques","volume":"13","author":"Rabezanahary","year":"2020","journal-title":"Mucosal Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1172\/JCI45157","article-title":"Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections","volume":"121","author":"Zeng","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s12250-007-0053-9","article-title":"Establishment of AIDS animal model with SIVmac239 infected Chinese rhesus monkey","volume":"22","author":"Li","year":"2007","journal-title":"Virol. Sin."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lu, Y., Zhang, M.X., Pang, W., Song, T.Z., Zheng, H.Y., Tian, R.R., and Zheng, Y.T. (2022). Transcription factor ZNF683 inhibits SIV\/HIV replication through regulating IFN\u03b3 secretion of CD8+ T Cells. Viruses, 14.","DOI":"10.3390\/v14040719"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1038\/s41423-022-00899-6","article-title":"Aging induces severe SIV infection accompanied by an increase in follicular CD8+ T cells with overactive STAT3 signaling","volume":"19","author":"Zheng","year":"2022","journal-title":"Cell. Mol. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1111\/imm.12574","article-title":"Translocation of microbes and changes of immunocytes in the gut of rapid- and slow-progressor Chinese rhesus macaques infected with SIVmac239","volume":"147","author":"Zhang","year":"2016","journal-title":"Immunology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2648891","DOI":"10.1080\/22221751.2026.2648891","article-title":"Development of a progressive HIV-1-Like infection model in northern pig-tailed macaques using stHIV-1sv\/G53D","volume":"15","author":"Song","year":"2026","journal-title":"Emerg. Microbes Infect."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1099\/0022-1317-82-9-2225","article-title":"In situ hybridization and immunolabelling study of the early replication of simian immunodeficiency virus (SIVmacJ5) in vivo","volume":"82","author":"Jones","year":"2001","journal-title":"J. Gen. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/1742-4690-6-106","article-title":"Dynamics of viral replication in blood and lymphoid tissues during SIVmac251 infection of macaques","volume":"6","author":"Mannioui","year":"2009","journal-title":"Retrovirology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e0080822","DOI":"10.1128\/jvi.00808-22","article-title":"Rapid loss of CD4 T cells by pyroptosis during acute SIV infection in rhesus macaques","volume":"96","author":"He","year":"2022","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e00371-19","DOI":"10.1128\/JVI.00371-19","article-title":"Differential dynamics of regulatory T-cell and Th17 cell balance in mesenteric lymph nodes and blood following early antiretroviral initiation during acute simian immunodeficiency virus infection","volume":"93","author":"Yero","year":"2019","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Liu, J., Xiao, Q., Zhou, R., Wang, Y., Xian, Q., Ma, T., Zhuang, K., Zhou, L., Guo, D., and Wang, X. (2016). Comparative analysis of immune activation markers of CD8+ T Cells in lymph nodes of different origins in SIV-infected Chinese rhesus macaques. Front. Immunol., 7.","DOI":"10.3389\/fimmu.2016.00371"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lederer, S., Favre, D., Walters, K.A., Proll, S., Kanwar, B., Kasakow, Z., Baskin, C.R., Palermo, R., McCune, J.M., and Katze, M.G. (2009). Transcriptional profiling in pathogenic and non-pathogenic SIV infections reveals significant distinctions in kinetics and tissue compartmentalization. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000296"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1111\/j.1600-0684.2006.00180.x","article-title":"Gene expression profiling of gut mucosa and mesenteric lymph nodes in simian immunodeficiency virus-infected macaques with divergent disease course","volume":"35","author":"George","year":"2006","journal-title":"J. Med. Primatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1086\/510852","article-title":"Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor \u03b21-positive regulatory T cells and begins in early infection","volume":"195","author":"Estes","year":"2007","journal-title":"J. Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.immuni.2014.10.004","article-title":"T follicular helper cell differentiation, function, and roles in disease","volume":"41","author":"Crotty","year":"2014","journal-title":"Immunity"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"eaag2285","DOI":"10.1126\/scitranslmed.aag2285","article-title":"Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies","volume":"9","author":"Petrovas","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Miles, B., Miller, S.M., Folkvord, J.M., Levy, D.N., Rakasz, E.G., Skinner, P.J., and Connick, E. (2016). Follicular regulatory CD8 T Cells impair the germinal center response in SIV and ex vivo HIV infection. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005924"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Moretti, S., Schietroma, I., Sberna, G., Maggiorella, M.T., Sernicola, L., Farcomeni, S., Giovanetti, M., Ciccozzi, M., and Borsetti, A. (2023). HIV-1-host interaction in gut-associated lymphoid tissue (GALT): Effects on local environment and comorbidities. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241512193"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1097\/COH.0b013e3282f9ae9c","article-title":"The mucosal barrier and immune activation in HIV pathogenesis","volume":"3","author":"Brenchley","year":"2008","journal-title":"Curr. Opin. HIV AIDS"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/18\/8\/855\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T04:11:20Z","timestamp":1786162280000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/18\/8\/855"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":23,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["v18080855"],"URL":"https:\/\/doi.org\/10.3390\/v18080855","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]}}}