{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:47:56Z","timestamp":1753890476997,"version":"3.41.2"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T00:00:00Z","timestamp":1658966400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The HIV-1 reservoir is a major barrier to curative strategies. Inflammation is an important factor for HIV-1 reservoir persistence. Lenalidomide regulates inflammatory cytokines efficiently. We examined whether lenalidomide could inhibit HIV-1 transcription and reduce systemic inflammation in people living with HIV.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Lenalidomide was administered orally for 48 weeks to patients with HIV-associated cryptococcal meningitis (HIV-CM). A HIV-1 latency model was treated with or without lenalidomide ex vivo for 5 days. The primary endpoints were change in HIV reservoir markers and inflammatory cytokines in both the cohort and cell model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thirteen participants were enrolled from May 2019 to September 2020. The median change in cell-associated (CA) HIV RNA between baseline and 48 weeks was 0.81 log10 copies\/million peripheral blood mononuclear cells (PBMCs). The CA HIV RNA decreased significantly in the cohort (P = 0.021). Serum tumor necrosis factor-\u03b1 (TNF-\u03b1) and interleukin-6 (IL-6) gradually diminished with lenalidomide treatment until 48 weeks (P\u2009=\u20090.007, P\u2009=\u20090.014, respectively). C-reactive protein\/IL-6\/TNF-\u03b1 and CA HIV RNA were significantly correlated (P = 0.0027, 0.0496, and 0.0346, respectively). Lenalidomide also significantly decreased HIV core P24 (P = 0.0038) and CA HIV RNA in CD8-depleted PBMCs (P = 0.0178) ex vivo. TNF-\u03b1 and IL-6 were significantly reduced in the CD8-depleted PBMC supernatant (P\u2009= 0.004, P\u2009&amp;lt;\u20090.0001, respectively) while IL-10 levels increased significantly on lenalidomide compared to no-lenalidomide treatment (P\u2009&amp;lt;\u20090.0001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Lenalidomide was preliminarily confirmed to reduce the level of cell- associated HIV RNA and improve persistent inflammation in patients with HIV-Associated cryptococcal meningitis, which was a potential intervention for clinical use to inhibit viral transcription of the HIV-1 reservoir and reduced HIV-related inflammation in HIV-1 patients during ART.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcimb.2022.954814","type":"journal-article","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T15:21:46Z","timestamp":1659021706000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Lenalidomide potentially reduced the level of cell- associated HIV RNA and improved persistent inflammation in patients with HIV-associated cryptococcal meningitis a pilot study"],"prefix":"10.3389","volume":"12","author":[{"given":"Xiang","family":"Liu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueling","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaorong","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ran","family":"Tao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhikai","family":"Wan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiangjin","family":"Hui","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongzheng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Hang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Biao","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.00424","article-title":"Block and lock hiv cure strategies to control the latent reservoir","volume":"10","author":"Ahlenstiel","year":"2020","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-7-15","article-title":"High systemic levels of interleukin-10, interleukin-22 and c-reactive protein in Indian patients are associated with low in vitro replication of HIV-1 subtype c viruses","volume":"7","author":"Arias","year":"2010","journal-title":"Retrovirology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1007\/s40265-020-01381-1","article-title":"Lenalidomide: A review in previously treated follicular lymphoma","volume":"80","author":"Blair","year":"2020","journal-title":"Drugs"},{"key":"B4","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/nm.3489","article-title":"New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo","volume":"20","author":"Bullen","year":"2014","journal-title":"Nat. Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1172\/JCI90745","article-title":"Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs","volume":"127","author":"Cheng","year":"2017","journal-title":"J. Clin. Invest."},{"key":"B6","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1016\/j.chom.2020.03.014","article-title":"The biology of the hiv-1 latent reservoir and implications for cure strategies","volume":"27","author":"Cohn","year":"2020","journal-title":"Cell Host Microbe"},{"key":"B7","doi-asserted-by":"publisher","first-page":"974","DOI":"10.1016\/j.jaad.2015.11.043","article-title":"Use of tumor necrosis factor (TNF) inhibitors in patients with HIV\/AIDS","volume":"74","author":"Gallitano","year":"2016","journal-title":"J. Am. Acad. Dermatol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1977","DOI":"10.1128\/AAC.02496-13","article-title":"Ruxolitinib and tofacitinib are potent and selective inhibitors of HIV-1 replication and virus reactivation in vitro","volume":"58","author":"Gavegnano","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"B9","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/j.it.2007.10.008","article-title":"Is HIV infection a TNF receptor signalling-driven disease","volume":"29","author":"Herbein","year":"2008","journal-title":"Trends Immunol."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0030881","article-title":"A plasma biomarker signature of immune activation in HIV patients on antiretroviral therapy","volume":"7","author":"Kamat","year":"2012","journal-title":"PloS One"},{"key":"B11","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1016\/j.celrep.2017.09.080","article-title":"In vivo suppression of HIV rebound by didehydro-cortistatin a, a \u201cBlock-and-Lock\u201d strategy for HIV-1 treatment","volume":"21","author":"Kessing","year":"2017","journal-title":"Cell Rep."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1186\/1756-8722-2-36","article-title":"Mechanism of action of lenalidomide in hematological malignancies","volume":"2","author":"Kotla","year":"2009","journal-title":"J. Hematol. Oncol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.3390\/v6041837","article-title":"HIV-1 latency in monocytes\/macrophages","volume":"6","author":"Kumar","year":"2014","journal-title":"Viruses"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1901","DOI":"10.1172\/JCI80142","article-title":"Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations","volume":"125","author":"Laird","year":"2015","journal-title":"J. Clin. Invest."},{"key":"B15","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1002\/ajh.25100","article-title":"A prospective phase II study of low dose lenalidomide plus dexamethasone in patients with newly diagnosed polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome","volume":"93","author":"Li","year":"2018","journal-title":"Am. J. Hematol."},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2021.108470","article-title":"Lenalidomide attenuates post-inflammation pulmonary fibrosis through blocking NF-\u03baB signaling pathway","volume":"103","author":"Li","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01328","article-title":"Monocyte-derived dendritic cells differentiated in the presence of lenalidomide display a semi-mature phenotype, enhanced phagocytic capacity, and th1 polarization capability","volume":"9","author":"L\u00f3pez-Rela\u00f1o","year":"2018","journal-title":"Front. Immunol."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/7316456","article-title":"HIV-Related immune activation and inflammation: current understanding and strategies","volume":"2021","author":"Lv","year":"2021","journal-title":"J. Immunol. Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1625","DOI":"10.1089\/aid.1997.13.1625","article-title":"A double-blind placebo-controlled phase II trial of thalidomide in asymptomatic HIV-positive patients: clinical tolerance and effect on activation markers and cytokines","volume":"13","author":"Marriott","year":"1997","journal-title":"AIDS Res. Hum. Retroviruses"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/842945","article-title":"Biological activity of lenalidomide and its underlying therapeutic effects in multiple myeloma","volume":"2012","author":"Martiniani","year":"2012","journal-title":"Adv. Hematol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.ebiom.2017.04.037","article-title":"Synergistic cytotoxicity of lenalidomide and dexamethasone in mantle cell lymphoma via cereblon-dependent targeting of the il-6\/stat3\/pi3k axis","volume":"20","author":"Ma","year":"2017","journal-title":"EBioMedicine"},{"key":"B22","doi-asserted-by":"publisher","first-page":"8280","DOI":"10.1096\/fj.201801165R","article-title":"The tat inhibitor didehydro-cortistatin a suppresses SIV replication and reactivation","volume":"33","author":"Mediouni","year":"2019","journal-title":"FASEB J."},{"key":"B23","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1080\/14656566.2018.1561865","article-title":"Lenalidomide for the treatment of mantle cell lymphoma","volume":"20","author":"Morabito","year":"2019","journal-title":"Expert Opin. Pharmacother."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01247-20","article-title":"The XPB subunit of the TFIIH complex plays a critical role in HIV-1 transcription and XPB inhibition by spironolactone prevents HIV-1 reactivation from latency","volume":"95","author":"Mori","year":"2020","journal-title":"J. Virol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"125","DOI":"10.12688\/f1000research.11881.1","article-title":"Exploiting immune cell metabolic machinery for functional HIV cure and the prevention of inflammaging","volume":"7","author":"Palmer","year":"2018","journal-title":"F1000Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3390\/v9040064","article-title":"Targeting TNF and TNF receptor pathway in HIV-1 infection: from immune activation to viral reservoirs","volume":"9","author":"Pasquereau","year":"2017","journal-title":"Viruses"},{"key":"B27","doi-asserted-by":"publisher","first-page":"846","DOI":"10.2174\/1568009617666170214104426","article-title":"Immunomodulatory drugs (imids) in multiple myeloma","volume":"17","author":"Raza","year":"2017","journal-title":"Curr. Cancer Drug Targets"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-8-80","article-title":"Expression and reactivation of HIV in a chemokine induced model of HIV latency in primary resting CD4+ T cells","volume":"8","author":"Saleh","year":"2011","journal-title":"Retrovirology"},{"key":"B29","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1016\/S1470-2045(20)30225-4","article-title":"Tafasitamab plus lenalidomide in relapsed or refractory diffuse large b-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study","volume":"21","author":"Salles","year":"2020","journal-title":"Lancet Oncol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1016\/j.immuni.2018.04.030","article-title":"Targeting the latent reservoir for hiv-1","volume":"48","author":"Sengupta","year":"2018","journal-title":"Immunity"},{"key":"B31","doi-asserted-by":"publisher","first-page":"6425","DOI":"10.1002\/jcp.26429","article-title":"Macrophage plasticity, polarization, and function in health and disease","volume":"233","author":"Shapouri-Moghaddam","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1093\/infdis\/jiu254","article-title":"Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment","volume":"210","author":"Tenorio","year":"2014","journal-title":"J. Infect. Dis."},{"key":"B33","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.cytogfr.2012.05.001","article-title":"The role of cytokines in the establishment, persistence and eradication of the HIV reservoir","volume":"23","author":"Vandergeeten","year":"2012","journal-title":"Cytokine Growth Factor Rev."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3390\/v12010084","article-title":"Block-and-lock strategies to cure hiv infection","volume":"12","author":"Vansant","year":"2020","journal-title":"Viruses"},{"key":"B35","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1172\/JCI89488","article-title":"Targeting type I interferon-mediated activation restores immune function in chronic HIV infection","volume":"127","author":"Zhen","year":"2017","journal-title":"J. Clin. Invest."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/v11030200","article-title":"Immune activation, inflammation, and non-AIDS Co-morbidities in HIV-infected patients under long-term ART","volume":"11","author":"Zicari","year":"2019","journal-title":"Viruses"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.954814\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T03:02:38Z","timestamp":1659063758000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2022.954814\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,28]]},"references-count":36,"alternative-id":["10.3389\/fcimb.2022.954814"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2022.954814","relation":{},"ISSN":["2235-2988"],"issn-type":[{"type":"electronic","value":"2235-2988"}],"subject":[],"published":{"date-parts":[[2022,7,28]]},"article-number":"954814"}}