{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:10:08Z","timestamp":1783123808713,"version":"3.54.6"},"reference-count":36,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T00:00:00Z","timestamp":1634169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Liver fibrosis is accelerated in patients coinfected with hepatitis C virus and human immunodeficiency virus (HIV), compared with HCV monoinfected patients, although the underlying mechanisms are unknown. We hypothesize that T cells expressing the HIV co-receptor, chemokine receptor 5 (CCR5), preferentially migrate to the inflamed liver and contribute to enhanced fibrogenesis. We compared the peripheral and intrahepatic CCR5 expression on CD4+ and CD8+ T cells in 21 HIV\/HCV-coinfected patients with 14 chronic HCV monoinfected patients. Using 12-color flow cytometry, phenotypic and functional characterization of CCR5+ and negative cells pre- and post-stimulation with HCV genotype specific overlapping pooled peptides was conducted. Patients with HIV\/HCV coinfection had significantly more CD4+CCR5+ and CD8+CCR5+ T cells in the liver as compared with peripheral blood (p = 0.0001 for both). Compared with patients with HCV monoinfection, patients with HIV\/HCV coinfection also had fewer peripheral CD4+CCR5+ and CD8+CCR5+ T cells (p = 0.02, p = 0.001 respectively), but more intrahepatic CD4+CCR5+ and CD8+CCR5+ cells (p = 0.0001 for both). Phenotypic analysis of CCR5+ sorted cells demonstrated an increased expression of markers of exhaustion, senescence, immune activation and liver homing (PD1, CD57, CD38, HLADR, and CXCR3). Post-stimulation with HCV peptides, CCR5+ T cells secreted more proinflammatory and profibrogenic cytokines and chemokines rather than antiviral cytokines. Phenotypic and functional analyses of CCR5+ T cells in HIV\/HCV-coinfected patients revealed a pathogenic role for CCR5+ T cells in hepatic fibrogenesis. These cells are functionally proinflammatory, pro-fibrogenic and preferentially accumulate in liver, accelerating fibrosis. These findings suggest that targeting CCR5 may be a therapeutic strategy for be ameliorating liver fibrosis.<\/jats:p>","DOI":"10.3390\/v13102074","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T23:02:16Z","timestamp":1634252536000},"page":"2074","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["CCR5+ T-Cells Homed to the Liver Exhibit Inflammatory and Profibrogenic Signatures in Chronic HIV\/HCV-Coinfected Patients"],"prefix":"10.3390","volume":"13","author":[{"given":"Shikha","family":"Shrivastava","sequence":"first","affiliation":[{"name":"Laboratory of Adjuvant and Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7471-0812","authenticated-orcid":false,"given":"Shyam","family":"Kottilil","sequence":"additional","affiliation":[{"name":"Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA"},{"name":"Program in Oncology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth E.","family":"Sherman","sequence":"additional","affiliation":[{"name":"Division of Digestive Diseases, University of Cincinnati, Cincinatti, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Masur","sequence":"additional","affiliation":[{"name":"National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8682-9220","authenticated-orcid":false,"given":"Lydia","family":"Tang","sequence":"additional","affiliation":[{"name":"Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA"},{"name":"Program in Oncology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1086\/339042","article-title":"Hepatitis C Virus Prevalence among Patients Infected with Human Immunodeficiency Virus: A Cross-Sectional Analysis of the US Adult AIDS Clinical Trials Group","volume":"34","author":"Sherman","year":"2002","journal-title":"Clin. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1097\/01.aids.0000192065.09281.01","article-title":"HIV, hepatitis C and HIV\/hepatitis C virus co-infection in vulnerable populations","volume":"19","author":"Backus","year":"2005","journal-title":"AIDS"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1086\/321909","article-title":"Influence of Human Immunodeficiency Virus Infection on the Course of Hepatitis C Virus Infection: A Meta-Analysis","volume":"33","author":"Graham","year":"2001","journal-title":"Clin. Infect. Dis."},{"key":"ref_4","first-page":"369","article-title":"Hepatic decompensation in antiretroviral-treated patients co-infected with HIV and hepatitis C virus compared with hepatitis C virus-monoinfected patients: A cohort study","volume":"160","author":"Kallan","year":"2014","journal-title":"Ann. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.jhep.2012.06.010","article-title":"All-cause and liver-related mortality in HIV positive subjects compared to the general population: Differences by HCV co-infection","volume":"57","author":"Hernando","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/nrgastro.2014.17","article-title":"HCV and HIV co-infection: Mechanisms and management","volume":"11","author":"Chen","year":"2014","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1086\/644771","article-title":"Meta-Analysis: Increased Mortality Associated with Hepatitis C in HIV-Infected Persons Is Unrelated to HIV Disease Progression","volume":"49","author":"Chen","year":"2009","journal-title":"Clin. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1093\/infdis\/jis926","article-title":"Pathogenesis of Accelerated Fibrosis in HIV\/HCV Co-infection","volume":"207","author":"Lin","year":"2013","journal-title":"J. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9184","DOI":"10.3390\/ijms15069184","article-title":"Molecular Mechanisms of Liver Fibrosis in HIV\/HCV Coinfection","volume":"15","author":"Mastroianni","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.jhep.2013.04.029","article-title":"Impaired CD4+ T cell stimulation of NK cell anti-fibrotic activity may contribute to accelerated liver fibrosis progression in HIV\/HCV patients","volume":"59","author":"Eisenhardt","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/381667a0","article-title":"HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5","volume":"381","author":"Dragic","year":"1996","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1126\/science.272.5270.1955","article-title":"CC CKR5: A RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1","volume":"272","author":"Alkhatib","year":"1996","journal-title":"Science"},{"key":"ref_13","first-page":"G949","article-title":"Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration","volume":"285","author":"Schwabe","year":"2003","journal-title":"Am. J. Physiol. Liver Physiol."},{"key":"ref_14","first-page":"1858","article-title":"CCR1 and CCR5 promote hepatic fibrosis in mice","volume":"119","author":"Seki","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.cyto.2007.05.013","article-title":"Chemokines in hepatitis C virus infection: Pathogenesis, prognosis and therapeutics","volume":"39","author":"Wald","year":"2007","journal-title":"Cytokine"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1093\/cid\/ciy807","article-title":"Improvement in Hepatic Fibrosis Biomarkers Associated With Chemokine Receptor Inactivation Through Mutation or Therapeutic Blockade","volume":"68","author":"Sherman","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1002\/hep.29477","article-title":"A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis","volume":"67","author":"Friedman","year":"2018","journal-title":"Hepatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6236","DOI":"10.4049\/jimmunol.163.11.6236","article-title":"Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver","volume":"163","author":"Shields","year":"1999","journal-title":"J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1111\/jvh.12702","article-title":"Augmentation of hepatitis C virus-specific immunity and sustained virologic response","volume":"24","author":"Shrivastava","year":"2017","journal-title":"J. Viral Hepat."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1086\/315315","article-title":"CD4+T Cell Surface CCR5 Density as a Determining Factor of Virus Load in Persons Infected with Human Immunodeficiency Virus Type 1","volume":"181","author":"Reynes","year":"2000","journal-title":"J. Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1111\/jvh.12291","article-title":"Hepatic compartmentalization of exhausted and regulatory cells in HIV\/HCV-coinfected patients","volume":"22","author":"Barrett","year":"2015","journal-title":"J. Viral Hepat."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1182\/blood-2002-07-2103","article-title":"Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells","volume":"101","author":"Brenchley","year":"2003","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Papagno, L., Spina, C.A., Marchant, A., Salio, M., Rufer, N., Little, S., Dong, T., Chesney, G., Waters, A., and Easterbrook, P. (2004). Immune Activation and CD8+ T-Cell Differentiation towards Senescence in HIV-1 Infection. PLoS Biol., 2.","DOI":"10.1371\/journal.pbio.0020020"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1097\/00002030-199905280-00004","article-title":"Expansion of CD57 and CD62L-CD45RA+ CD8 T lymphocytes correlates with reduced viral plasma RNA after primary HIV infection","volume":"13","author":"Lieberman","year":"1999","journal-title":"AIDS"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2908","DOI":"10.1002\/(SICI)1521-4141(199909)29:09<2908::AID-IMMU2908>3.0.CO;2-8","article-title":"Distribution of human CMV-specific memory T cells among the CD8pos. subsets defined by CD57, CD27, and CD45 isoforms","volume":"29","author":"Kern","year":"1999","journal-title":"Eur. J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.ebiom.2018.01.028","article-title":"IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and Reversal","volume":"29","author":"Weng","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2861","DOI":"10.1111\/j.1572-0241.2002.07054.x","article-title":"Increased expression of T cell chemokines and their receptors in chronic hepatitis C: Relationship with the histological activity of liver disease","volume":"97","author":"Apolinario","year":"2002","journal-title":"Am. J. Gastroenterol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.jhep.2007.04.009","article-title":"The role of CCR5\/CXCR3 expressing CD8+ cells in liver damage and viral control during persistent hepatitis C virus infection","volume":"47","author":"Larrubia","year":"2007","journal-title":"J. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4129","DOI":"10.1172\/JCI41732","article-title":"Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice","volume":"120","author":"Berres","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1182\/blood-2005-01-0126","article-title":"Plasma chemokine levels correlate with the outcome of antiviral therapy in patients with hepatitis C","volume":"106","author":"Butera","year":"2005","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1128\/JVI.01388-08","article-title":"Differential Expression of the CXCR3 Ligands in Chronic Hepatitis C Virus (HCV) Infection and Their Modulation by HCV In Vitro","volume":"83","author":"Helbig","year":"2009","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.jhep.2010.12.033","article-title":"Induction of CXCR3- and CCR5-associated chemokines during acute hepatitis C virus infection","volume":"55","author":"Zeremski","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4721","DOI":"10.1128\/AAC.49.11.4721-4732.2005","article-title":"Maraviroc (UK-427,857), a Potent, Orally Bioavailable, and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 Activity","volume":"49","author":"Dorr","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1038\/nm1319","article-title":"Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1","volume":"11","author":"Pozniak","year":"2005","journal-title":"Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1002\/hep4.1160","article-title":"Prolonged cenicriviroc therapy reduces hepatic fibrosis despite steatohepatitis in a diet-induced mouse model of nonalcoholic steatohepatitis","volume":"2","author":"Kruger","year":"2018","journal-title":"Hepatol. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1002\/hep.31108","article-title":"Cenicriviroc Treatment for Adults with Nonalcoholic Steatohepatitis and Fibrosis: Final Analysis of the Phase 2b CENTAUR Study","volume":"72","author":"Ratziu","year":"2020","journal-title":"Hepatology"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/10\/2074\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:14:53Z","timestamp":1760166893000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/10\/2074"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,14]]},"references-count":36,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["v13102074"],"URL":"https:\/\/doi.org\/10.3390\/v13102074","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,14]]}}}