{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T03:40:41Z","timestamp":1789875641330,"version":"4.0.1"},"reference-count":45,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2019,1,27]],"date-time":"2019-01-27T00:00:00Z","timestamp":1548547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI093307"],"award-info":[{"award-number":["R01 AI093307"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS104016"],"award-info":[{"award-number":["R01 NS104016"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"publisher","award":["R01MH116844"],"award-info":[{"award-number":["R01MH116844"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Understanding HIV latent reservoirs in tissues is essential for the development of new strategies targeting these sites for eradication. Here, we assessed the size of latent reservoirs and the source of residual viruses in multiple lymphoid tissues of SIV-infected and fully suppressed rhesus macaques of Chinese-origin (cRMs). Eight cRMs were infected with SIVmac251 and treated with tenofovir and emtricitabine daily for 24 weeks initiated 4 weeks post-infection. Four of the eight animals reached sustained full viral suppression with undetectable viremia. The levels of cell-associated SIV DNA varied in peripheral blood mononuclear cells (PBMCs) and multiple lymphoid tissues, but with higher levels in the mesenteric lymph nodes (MesLNs). The levels of cell-associated SIV RNA also varied in different tissues. The higher frequency of viral RNA detection in the MesLNs was also observed by in situ hybridization. Consistently, the infection unit per million cells (IUPM) in the MesLNs was higher than in PBMCs and other tested lymphoid tissues by quantitative viral outgrowth assay (QVOA). Furthermore, env gp120 from tissue SIV RNA was amplified by single genome amplification. Phylogenetic analysis revealed diverse variants from tissues parallel to the viral inoculum in all viral suppressed animals. These results demonstrate that the latency and viral reservoirs in the lymphoid tissues still exist in aviremic macaques under full suppressive therapy. Moreover, the size of viral latent reservoirs differs in various lymphoid tissues with a relatively larger size in the MesLNs.<\/jats:p>","DOI":"10.3390\/v11020105","type":"journal-article","created":{"date-parts":[[2019,1,29]],"date-time":"2019-01-29T03:40:55Z","timestamp":1548733255000},"page":"105","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Persistent Viral Reservoirs in Lymphoid Tissues in SIV-Infected Rhesus Macaques of Chinese-Origin on Suppressive Antiretroviral Therapy"],"prefix":"10.3390","volume":"11","author":[{"given":"Summer","family":"Siddiqui","sequence":"first","affiliation":[{"name":"Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Perez","sequence":"additional","affiliation":[{"name":"Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Immunology, Schulich School of Medicine &amp; Dentistry, University of Western Ontario, London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Doyle-Meyers","sequence":"additional","affiliation":[{"name":"Division of Veterinary Medicine, Tulane National Primate Research Center, Covington, LA 70433, USA"},{"name":"Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian T","family":"Foley","sequence":"additional","affiliation":[{"name":"Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4101-4073","authenticated-orcid":false,"given":"Qingsheng","family":"Li","sequence":"additional","affiliation":[{"name":"Nebraska Center for Virology, School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binhua","family":"Ling","sequence":"additional","affiliation":[{"name":"Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433, USA"},{"name":"Tulane Center for Aging, Tulane University School of Medicine, New Orleans, LA 70112, USA"},{"name":"Department of Microbiology &amp; Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.immuni.2012.08.010","article-title":"Redefining the Viral Reservoirs that Prevent HIV-1 Eradication","volume":"37","author":"Eisele","year":"2012","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Henrich, T.J., Hatano, H., Bacon, O., Hogan, L.E., Rutishauser, R., Hill, A., Kearney, M.F., Anderson, E.M., Buchbinder, S.P., and Cohen, S.E. (2017). HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: An observational study. PLoS Med., 14.","DOI":"10.1371\/journal.pmed.1002417"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/nature13594","article-title":"Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys","volume":"512","author":"Whitney","year":"2014","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1038\/s41591-018-0026-6","article-title":"Rapid HIV RNA rebound after antiretroviral treatment interruption in persons durably suppressed in Fiebig I acute HIV infection","volume":"24","author":"Colby","year":"2018","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/nrmicro.2015.5","article-title":"HIV reservoirs: What, where and how to target them","volume":"14","author":"Churchill","year":"2016","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/nm.3781","article-title":"B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers","volume":"21","author":"Fukazawa","year":"2015","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Heesters, B.A., Lindqvist, M., Vagefi, P.A., Scully, E.P., Schildberg, F.A., Altfeld, M., Walker, B.D., Kaufmann, D.E., and Carroll, M.C. (2015). Follicular Dendritic Cells Retain Infectious HIV in Cycling Endosomes. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1005285"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1016\/j.tim.2016.02.006","article-title":"TFH in HIV Latency and as Sources of Replication-Competent Virus","volume":"24","author":"Miles","year":"2016","journal-title":"Trends Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/nature16933","article-title":"Persistent HIV-1 replication maintains the tissue reservoir during therapy","volume":"530","author":"Fryer","year":"2016","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.virol.2011.11.024","article-title":"Lymph nodes harbor viral reservoirs that cause rebound of plasma viremia in SIV-infected macaques upon cessation of combined antiretroviral therapy","volume":"423","author":"Horiike","year":"2012","journal-title":"Virology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"68","DOI":"10.20411\/pai.v1i1.100","article-title":"Defining HIV and SIV Reservoirs in Lymphoid Tissues","volume":"1","author":"Deleage","year":"2016","journal-title":"Pathog. Immun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1007\/s13365-017-0594-0","article-title":"Persistence of SIV in the brain of SIV-infected Chinese rhesus macaques with or without antiretroviral therapy","volume":"24","author":"Perez","year":"2018","journal-title":"J. Neurovirol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1097\/QAI.0b013e318266be53","article-title":"Characterization of peripheral and mucosal immune responses in rhesus macaques on long-term tenofovir and emtricitabine combination antiretroviral therapy","volume":"61","author":"Jasny","year":"2012","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ling, B., Piatak, M., Rogers, L., Johnson, A.M., Russell-Lodrigue, K., Hazuda, D.J., Lifson, J.D., and Veazey, R.S. (2014). Effects of treatment with suppressive combination antiretroviral drug therapy and the histone deacetylase inhibitor suberoylanilide hydroxamic acid; (SAHA) on SIV-infected Chinese rhesus macaques. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0102795"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1089\/aid.2012.0378","article-title":"Effect of combination antiretroviral therapy on Chinese rhesus macaques of simian immunodeficiency virus infection","volume":"29","author":"Ling","year":"2013","journal-title":"AIDS Res. Hum. Retroviruses"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/jmp.12088","article-title":"Optimization of PCR for quantification of simian immunodeficiency virus genomic RNA in plasma of rhesus macaques (Macaca mulatta) using armored RNA","volume":"43","author":"Monjure","year":"2014","journal-title":"J. Med. Primatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1038\/nature03513","article-title":"Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells","volume":"434","author":"Li","year":"2005","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1128\/JVI.01396-06","article-title":"Novel pathway for induction of latent virus from resting CD4(+) T cells in the simian immunodeficiency virus\/macaque model of human immunodeficiency virus type 1 latency","volume":"81","author":"Shen","year":"2007","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"ofv123","DOI":"10.1093\/ofid\/ofv123","article-title":"Designing and Interpreting Limiting Dilution Assays: General Principles and Applications to the Latent Reservoir for Human Immunodeficiency Virus-1","volume":"2","author":"Rosenbloom","year":"2015","journal-title":"Open Forum. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4584","DOI":"10.1128\/JVI.03507-12","article-title":"Comparative characterization of transfection- and infection-derived simian immunodeficiency virus challenge stocks for in vivo nonhuman primate studies","volume":"87","author":"Scarlotta","year":"2013","journal-title":"J. Virol"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1093\/molbev\/msw054","article-title":"MEGA7: Molecular Evolutionary Genetics Analysis Version 7.0 for Bigger Datasets","volume":"33","author":"Kumar","year":"2016","journal-title":"Mol Biol Evol"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1128\/CMR.00015-16","article-title":"Total HIV-1 DNA, a Marker of Viral Reservoir Dynamics with Clinical Implications","volume":"29","author":"Hocqueloux","year":"2016","journal-title":"Clin Microbiol Rev"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12977-018-0412-7","article-title":"Total HIV DNA: A global marker of HIV persistence","volume":"15","author":"Rouzioux","year":"2018","journal-title":"Retrovirology"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Deere, J.D., Kauffman, R.C., Cannavo, E., Higgins, J., Villalobos, A., Adamson, L., Schinazi, R.F., Luciw, P.A., and North, T.W. (2014). Analysis of multiply spliced transcripts in lymphoid tissue reservoirs of rhesus macaques infected with RT-SHIV during HAART. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087914"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/387183a0","article-title":"Quanitification of latent tissue reservoirs and total body viral load in HIV-1 infection","volume":"387","author":"Chun","year":"1997","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Josefsson, L., von Stockenstrom, S., Faria, N.R., Sinclair, E., Bacchetti, P., Killian, M., Epling, L., Tan, A., Ho, T., and Lemey, P. (2013). The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time. Proc Natl Acad Sci USA.","DOI":"10.1073\/pnas.1308313110"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5407","DOI":"10.1038\/ncomms6407","article-title":"Progressive contraction of the latent HIV reservoir around a core of less-differentiated CD4(+) memory T Cells","volume":"5","author":"Jaafoura","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s13365-017-0567-3","article-title":"Humanized mice: Models for evaluating NeuroHIV and cure strategies","volume":"24","author":"Honeycutt","year":"2017","journal-title":"J. Neurovirol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"179","DOI":"10.20411\/pai.v2i2.204","article-title":"HIV Infection of Macrophages: Implications for Pathogenesis and Cure","volume":"2","author":"Clayton","year":"2017","journal-title":"Pathog. Immun."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Gama, L., Abreu, C., Shirk, E.N., Queen, S.E., Beck, S.E., Metcalf Pate, K.A., Bullock, B.T., Zink, M.C., Mankowski, J.L., and Clements, J.E. (2018). SIV Latency in Macrophages in the CNS. Curr. Top Microbiol. Immunol.","DOI":"10.1007\/82_2018_89"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s12977-017-0344-7","article-title":"A mature macrophage is a principal HIV-1 cellular reservoir in humanized mice after treatment with long acting antiretroviral therapy","volume":"14","author":"Arainga","year":"2017","journal-title":"Retrovirology"},{"key":"ref_32","first-page":"15","article-title":"Follicular dendritic cells are a major reservoir for human immunodeficiency virus type 1 in lymphoid tissues facilitating infection of CD4+ T-helper cells","volume":"140","author":"Spiegel","year":"1992","journal-title":"Am. J. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/j.cell.2013.09.020","article-title":"Replication-Competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 Cure","volume":"155","author":"Ho","year":"2013","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1126\/science.1256304","article-title":"HIV latency. Proliferation of cells with HIV integrated into cancer genes contributes to persistent infection","volume":"345","author":"Wagner","year":"2014","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1126\/science.1254194","article-title":"HIV latency. Specific HIV integration sites are linked to clonal expansion and persistence of infected cells","volume":"345","author":"Maldarelli","year":"2014","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/s41591-018-0017-7","article-title":"Clonal CD4(+) T cells in the HIV-1 latent reservoir display a distinct gene profile upon reactivation","volume":"24","author":"Cohn","year":"2018","journal-title":"Nat. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3250","DOI":"10.1172\/JCI26197","article-title":"HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir","volume":"115","author":"Chun","year":"2005","journal-title":"J. Clin. Invest."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1073\/pnas.1318249111","article-title":"Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues","volume":"111","author":"Fletcher","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1073\/pnas.1522675113","article-title":"Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo","volume":"113","author":"Simonetti","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/71577","article-title":"The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy","volume":"6","author":"Ramratnam","year":"2000","journal-title":"Nat. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"16725","DOI":"10.1073\/pnas.0804192105","article-title":"HIV rebounds from latently infected cells, rather than from continuing low-level replication","volume":"105","author":"Joos","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1084\/jem.20060227","article-title":"Mesenteric lymph nodes at the center of immune anatomy","volume":"203","author":"Macpherson","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4789","DOI":"10.1128\/JVI.03367-12","article-title":"No viral evolution in the lymph nodes of simian immunodeficiency virus-infected rhesus macaques during combined antiretroviral therapy","volume":"87","author":"Oue","year":"2013","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Chun, T.W., Shawn Justement, J., Murray, D., Kim, C.J., Blazkova, J., Hallahan, C.W., Benko, E., Costiniuk, C.T., Kandel, G., and Ostrowski, M. (2013). Effect of Antiretroviral Therapy on HIV Reservoirs in Elite Controllers. J. Infect. Dis.","DOI":"10.1093\/infdis\/jit306"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"12971","DOI":"10.1128\/JVI.00387-10","article-title":"HIV-1 continues to replicate and evolve in patients with natural control of HIV infection","volume":"84","author":"Mens","year":"2010","journal-title":"J. Virol."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/11\/2\/105\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:28:55Z","timestamp":1760185735000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/11\/2\/105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,27]]},"references-count":45,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2019,2]]}},"alternative-id":["v11020105"],"URL":"https:\/\/doi.org\/10.3390\/v11020105","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,27]]}}}