{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:42:15Z","timestamp":1760402535780,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,8]],"date-time":"2022-01-08T00:00:00Z","timestamp":1641600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Recherche Et D\u00e9veloppement en Pathologies Infectieuses et Tropicales (REDPIT), France","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Raltegravir (RLT) prevents the integration of HIV DNA in the nucleus, but published studies remain controversial, suggesting that it does not decrease proviral DNA. However, there are only a few studies focused on virus-targeted cells. We aimed our study on the impact of RLT inclusion on total intra-cellular viral DNA (TID) in cellular subsets and immune effects in patients with newly acquired undetectable plasmatic viral load (UVL). Six patients having UVL using an antiretroviral combination for 6 months and CD4 T-cells &gt; 350\/mL and &lt;500\/mL were selected to receive RLT for 3 months from M0 to M3. Patients had 7 sequential viro-immunological determinations from M-1 to M5. Immune phenotypes were determined by flow cytometry and TID quantification was performed using PCR assay on purified cells. TID (median values) at the initiation of RLT in CD4 T-cells was 117 copies\/millions of cells, decreased to 27.5 on M3, and remained thereafter permanently under the cut-off (&lt;10 copies\/millions of cells) in 4 out of 6 patients. This was associated with an increase of CD4 and CD4 + CD28+ T-cells and a decrease of HLA-DR expression and apoptosis of CD4 T-cells. RLT inclusion led to decreases in the viral load along with positive immune reconstitution, mainly for CD4 T-cells in HIV patients.<\/jats:p>","DOI":"10.3390\/cells11020208","type":"journal-article","created":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T20:29:26Z","timestamp":1641760166000},"page":"208","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Raltegravir Inclusion Decreases CD4 T-Cells Intra-Cellular Viral Load and Increases CD4 and CD28 Positive T-Cells in Selected HIV Patients"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5464-6518","authenticated-orcid":false,"given":"Gaurav","family":"Kumar","sequence":"first","affiliation":[{"name":"Unit\u00e9 576, Centre Hospitalier Universitaire de Nice, Institut National de la Sante et de la Recherche Medicale, Universite de Nice-Sophia-Antipolis, 06200 Nice, France"},{"name":"Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacqueline","family":"Cottalorda-Dufayard","sequence":"additional","affiliation":[{"name":"Virologie, Hopital l\u2019Archet 2, Centre Hospitalier Universitaire de Nice, Universite de Nice-Sophia-Antipolis, 06200 Nice, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodolphe","family":"Garraffo","sequence":"additional","affiliation":[{"name":"Pharmacologie, Hopital Pasteur, Centre Hospitalier Universitaire de Nice, Universite de Nice-Sophia-Antipolis, 06200 Nice, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francine","family":"De Salvador-Guillou\u00ebt","sequence":"additional","affiliation":[{"name":"Infectiologie, Hopital l\u2019Archet 1, Centre Hospitalier Universitaire de Nice, Universite de Nice-Sophia-Antipolis, 06200 Nice, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Cua","sequence":"additional","affiliation":[{"name":"Infectiologie, Hopital l\u2019Archet 1, Centre Hospitalier Universitaire de Nice, Universite de Nice-Sophia-Antipolis, 06200 Nice, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierre-Marie","family":"Roger","sequence":"additional","affiliation":[{"name":"Unit\u00e9 576, Centre Hospitalier Universitaire de Nice, Institut National de la Sante et de la Recherche Medicale, Universite de Nice-Sophia-Antipolis, 06200 Nice, France"},{"name":"Infectiologie, Hopital l\u2019Archet 1, Centre Hospitalier Universitaire de Nice, Universite de Nice-Sophia-Antipolis, 06200 Nice, France"},{"name":"Service Des Maladies Infectieuses et Tropicales, Centre Hospitalier Universitaire de Pointe-\u00e0-Pitre, 97159 Pointe-\u00e0-Pitre, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1001\/jama.296.7.827","article-title":"Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel","volume":"296","author":"Hammer","year":"2006","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1056\/NEJMoa1110187","article-title":"Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy","volume":"368","author":"Le","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1097\/00002030-200305020-00004","article-title":"The potential for CD4 cell increases in HIV-positive individuals who control viraemia with highly active antiretroviral therapy","volume":"17","author":"Smith","year":"2003","journal-title":"AIDS"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1086\/605890","article-title":"Serum immune activation markers are persistently increased in patients with HIV infection after 6 years of antiretroviral therapy despite suppression of viral replication and reconstitution of CD4+ T cells","volume":"200","author":"French","year":"2009","journal-title":"J. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4739","DOI":"10.1038\/s41467-019-12732-2","article-title":"Resident memory T cells are a cellular reservoir for HIV in the cervical mucosa","volume":"10","author":"Rosero","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1189\/jlb.0306150","article-title":"Monocyte-derived macrophages and myeloid cell lines as targets of HIV-1 replication and persistence","volume":"80","author":"Cassol","year":"2006","journal-title":"J. Leukoc. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1038\/nm1295-1284","article-title":"In vivo fate of HIV-1-infected T cells: Quantitative analysis of the transition to stable latency","volume":"1","author":"Chun","year":"1995","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1111\/j.1750-3639.2003.tb00010.x","article-title":"HIV-1 persistence, viral reservoir, and the central nervous system in the HAART era","volume":"13","author":"Lambotte","year":"2003","journal-title":"Brain Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1126\/science.278.5341.1295","article-title":"Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy","volume":"278","author":"Finzi","year":"1997","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1086\/338256","article-title":"Reservoirs of human immunodeficiency virus type 1: The main obstacles to viral eradication","volume":"34","author":"Pomerantz","year":"2002","journal-title":"Clin. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Siliciano, J.D., and Siliciano, R.F. (2021). In Vivo Dynamics of the Latent Reservoir for HIV-1: New Insights and Implications for Cure. Annu Rev. Pathol.","DOI":"10.1146\/annurev-pathol-050520-112001"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.virol.2020.01.006","article-title":"Transcriptional profiling indicates cAMP-driven reversal of HIV latency in monocytes occurs via transcription factor SP-1","volume":"542","author":"Moar","year":"2020","journal-title":"Virology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/nm0298-208","article-title":"Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: A composite of redistribution and proliferation","volume":"4","author":"Pakker","year":"1998","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1111\/j.1468-1293.2005.00307.x","article-title":"Dysregulation of CD28 and CTLA-4 expression by CD4 T cells from previously immunodeficient HIV-infected patients with sustained virological responses to highly active antiretroviral therapy","volume":"6","author":"Stone","year":"2005","journal-title":"HIV Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/j.1365-2249.1994.tb07015.x","article-title":"Selective increase of activation antigens HLA-DR and CD38 on CD4 + CD45RO + T lymphocytes during HIV-1 infection","volume":"95","author":"Kestens","year":"1994","journal-title":"Clin. Exp. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1097\/00002030-200203080-00002","article-title":"CTLA-4 upregulation during HIV infection: Association with anergy and possible target for therapeutic intervention","volume":"16","author":"Leng","year":"2002","journal-title":"AIDS"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1097\/00002030-199902040-00008","article-title":"Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. INCAS Study Group","volume":"13","author":"Pakker","year":"1999","journal-title":"AIDS"},{"key":"ref_18","first-page":"1194","article-title":"Expansion of a CD8+ CD28-cell population in the blood and lung of HIV-positive patients","volume":"6","author":"Saukkonen","year":"1993","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1111\/j.1365-2249.1995.tb03717.x","article-title":"Increased cytolytic T lymphocyte activity and decreased B7 responsiveness are associated with CD28 down-regulation on CD8+ T cells from HIV-infected subjects","volume":"100","author":"Vingerhoets","year":"1995","journal-title":"Clin. Exp. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1097\/00002030-199404000-00004","article-title":"Lymphocyte activation in HIV-1 infection. II. Functional defects of CD28- T cells","volume":"8","author":"Borthwick","year":"1994","journal-title":"AIDS"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s004300050010","article-title":"Expansion of T cells negative for CD28 expression in HIV infection. Relation to activation markers and cell adhesion molecules, and correlation with prognostic markers","volume":"185","author":"Kammerer","year":"1996","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3509","DOI":"10.4049\/jimmunol.156.9.3509","article-title":"Programmed cell death in peripheral lymphocytes from HIV-infected persons: Increased susceptibility to apoptosis of CD4 and CD8 T cells correlates with lymphocyte activation and with disease progression","volume":"156","author":"Gougeon","year":"1996","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1126\/science.276.5314.960","article-title":"Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection","volume":"276","author":"Cavert","year":"1997","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1128\/JCM.40.6.2089-2094.2002","article-title":"Detection of replication-competent human immunodeficiency virus type 1 (HIV-1) in cultures from patients with levels of HIV-1 RNA in plasma suppressed to less than 500 or 50 copies per milliliter","volume":"40","author":"Demeter","year":"2002","journal-title":"J. Clin. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1038\/71569","article-title":"Persistence of episomal HIV-1 infection intermediates in patients on highly active anti-retroviral therapy","volume":"6","author":"Sharkey","year":"2000","journal-title":"Nat. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/S0140-6736(09)62041-9","article-title":"Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): Two multicentre, double-blind, randomised controlled trials","volume":"375","author":"Eron","year":"2010","journal-title":"Lancet"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1086\/597290","article-title":"Raltegravir: The first HIV type 1 integrase inhibitor","volume":"48","author":"Hicks","year":"2009","journal-title":"Clin. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/S0140-6736(09)60918-1","article-title":"Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: A multicentre, double-blind randomised controlled trial","volume":"374","author":"Lennox","year":"2009","journal-title":"Lancet"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1097\/QAD.0b013e328359f20f","article-title":"Raltegravir intensification shows differing effects on CD8 and CD4 T cells in HIV-infected HAART-suppressed individuals with poor CD4 T-cell recovery","volume":"26","author":"Massanella","year":"2012","journal-title":"AIDS"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1080\/14787210.2020.1733415","article-title":"Real word outcomes associated with use of raltegravir in older people living with HIV: Results from the 60 months follow-up of the RAL-age cohort","volume":"18","author":"Santinelli","year":"2020","journal-title":"Expert Rev. Anti Infect. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1128\/jvi.70.1.199-206.1996","article-title":"Upregulation of Fas ligand expression by human immunodeficiency virus in human macrophages mediates apoptosis of uninfected T lymphocytes","volume":"70","author":"Badley","year":"1996","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/nm0295-129","article-title":"Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes","volume":"1","author":"Finkel","year":"1995","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8927","DOI":"10.1073\/pnas.1332627100","article-title":"Anti-nerve growth factor Ab abrogates macrophage-mediated HIV-1 infection and depletion of CD4+ T lymphocytes in hu-SCID mice","volume":"100","author":"Garaci","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1086\/338573","article-title":"Early CD4(+) T cell recovery in human immunodeficiency virus-infected patients receiving effective therapy is related to a down-regulation of apoptosis and not to proliferation","volume":"185","author":"Roger","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1097\/QAD.0b013e32834b9658","article-title":"Impact of treatment with raltegravir during primary or chronic HIV infection on RNA decay characteristics and the HIV viral reservoir","volume":"25","author":"Koelsch","year":"2011","journal-title":"AIDS"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1097\/QAD.0b013e3283584521","article-title":"The effect of intensification with raltegravir on the HIV-1 reservoir of latently infected memory CD4 T cells in suppressed patients","volume":"26","author":"Vallejo","year":"2012","journal-title":"AIDS"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1097\/QAD.0b013e32833d214c","article-title":"Time course of total HIV-1 DNA and 2-long-terminal repeat circles in patients with controlled plasma viremia switching to a raltegravir-containing regimen","volume":"24","author":"Delaugerre","year":"2010","journal-title":"AIDS"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1093\/infdis\/jiq138","article-title":"A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response","volume":"203","author":"Hatano","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Lam, Y.M., McBride, K.L., Amin, J., Cordery, D.V., Kelleher, A.D., Cooper, D.A., and Koelsch, K.K. (2012). Switching virally suppressed, treatment-experienced patients to a raltegravir-containing regimen does not alter levels of HIV-1 DNA. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0031990"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/nm.2111","article-title":"HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects","volume":"16","author":"Buzon","year":"2010","journal-title":"Nat. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"19851","DOI":"10.1073\/pnas.0810032105","article-title":"HIV infection-associated immune activation occurs by two distinct pathways that differentially affect CD4 and CD8 T cells","volume":"105","author":"Catalfamo","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1097\/QAD.0b013e328348065a","article-title":"Clinical efficacy of raltegravir against B and non-B subtype HIV-1 in phase III clinical studies","volume":"25","author":"Rockstroh","year":"2011","journal-title":"AIDS"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1097\/QAD.0b013e32834e8955","article-title":"Effect of raltegravir intensification on HIV proviral DNA in the blood and gut mucosa of men on long-term therapy: A randomized controlled trial","volume":"26","author":"Chege","year":"2012","journal-title":"AIDS"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1128\/AAC.00789-10","article-title":"Plasma and intracellular (peripheral blood mononuclear cells) pharmacokinetics of once-daily raltegravir (800 milligrams) in HIV-infected patients","volume":"55","author":"Molto","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1093\/jac\/dkr151","article-title":"Cell disposition of raltegravir and newer antiretrovirals in HIV-infected patients: High inter-individual variability in raltegravir cellular penetration","volume":"66","author":"Buclin","year":"2011","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1097\/QAI.0b013e3182364c67","article-title":"Plasma and intracellular pharmacokinetics of darunavir\/ritonavir once daily and raltegravir once and twice daily in HIV-infected individuals","volume":"58","author":"Jackson","year":"2011","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s12977-017-0370-5","article-title":"Reduced antiretroviral drug efficacy and concentration in HIV-infected microglia contributes to viral persistence in brain","volume":"14","author":"Asahchop","year":"2017","journal-title":"Retrovirology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1097\/QAD.0000000000000408","article-title":"The importance of monocytes and macrophages in HIV pathogenesis, treatment, and cure","volume":"28","author":"Campbell","year":"2014","journal-title":"AIDS"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.antiviral.2011.08.008","article-title":"Comparative antiviral activity of integrase inhibitors in human monocyte-derived macrophages and lymphocytes","volume":"92","author":"Scopelliti","year":"2011","journal-title":"Antivir. Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/2\/208\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:38:16Z","timestamp":1760362696000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/2\/208"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,8]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["cells11020208"],"URL":"https:\/\/doi.org\/10.3390\/cells11020208","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2022,1,8]]}}}