Skip to content
2000
image of Ferroptosis and Dysfunction of CD3+CD4−CD8− T Cells are Associated with Poor Immune Reconstitution in HIV Patients

Abstract

Introduction

Some HIV patients stay in an immune unresponsive state after antiretroviral therapy (ART), with a notably higher risk of AIDS-related and non-AIDS-related complications. Double-negative T cells (DNT) can compensate for immunity and prevent immune overactivation in HIV patients. Also, immune non-responders (INRs) have fewer DNT cells than immune responders (IRs). HIV infection and ART can change the dynamic function of cell mitochondria, which are crucial in ferroptosis. Ferroptosis is a form of cell death marked by the accumulation of reactive oxygen species (ROS) and iron-dependent lipid peroxidation. Yet, the changes in DNT cell function in INRs and the impact of ferroptosis on immune reconstitution remain unclear.

Aims

Our study focused on the expression level of DNT cells in HIV immune non-responders. Then, we detected markers of ferroptosis, cell activation, proliferation, killing function, and inflammatory states of DNT cells in INRs.

Methods

The study involved 88 PLHIVs who had received antiretroviral therapy for over 4 years and tested virus-negative. These patients were classified into two groups: 28 INRs (CD4 < 350/μl) and 60 IRs (CD4 ≥350/μl). Additionally, 25 sex- and age-matched HCs were included. Flow cytometry was used to detect ferroptosis markers (JC-1, Lipid ROS, lipid peroxidation), cell proliferation, and cell activation. Transmission electron microscopy (TEM) was applied to observe mitochondrial morphology. Finally, statistical analysis was performed on the detection results.

Results

After long-term antiretroviral therapy, we found that INRs had a lower DNT cell count than IRs. Regarding proliferation and activation, our results showed higher CD38/HLA-DR co-expression and Ki67 expression in INRs' DNT cells than in IRs', indicating over-activation of DNT cells in INRs. In terms of killing function, the perforin and granzyme B levels in INRs' DNT cells were lower than those in IRs', suggesting impaired killing function of DNT cells in INRs. For ferroptosis, the proportion of DNT cells with decreased MMP in INRs was higher than in IRs and HCs. INRs' DNT cells also had higher levels of lipid ROS and lipid peroxidation compared to those in IRs and HCs. TEM revealed that the mitochondria of INRs' DNT cells had typical morphological features. Moreover, INRs' DNT cells had a greater degree of inflammation.

Conclusion

Our study centered on the proliferation, activation, ferroptosis, killing function, and inflammatory status of DNT cells in INRs. We found that DNT cells in INRs had more active proliferation and activation, weakened killing function, mitochondrial function with typical ferroptosis features, and increased TNF-αlevels. Correlation analysis indicated that DNT cell overactivation (Ki-67+, CD38+HLA-DR+), MMP reduction ratio, and TNF-αexpression were negatively related to immune reconstitution in PLHIVs. In contrast, the killing function (perforin+) of DNT cells was positively related to it. These findings provide a theoretical basis for targeting the functional remodeling of DNT cells. In the future, therapeutic strategies can be explored, such as regulating the mitochondrial metabolic pathway or enhancing the immunoregulatory activity of DNT cells. These strategies can thus offer innovative solutions to the dilemma of immune reconstitution in HIV-infected individuals.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/chr/10.2174/011570162X366300250509112302
2025-05-20
2025-09-04

  • From This Site

    /content/journals/chr/10.2174/011570162X366300250509112302
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Gazzola L. Tincati C. Bellistre G.M. d’Arminio Monforte A. Marchetti G. The absence of CD4+ T cell count recovery despite receipt of virologically suppressive highly active antiretroviral therapy: Clinical risk, immunological gaps, and therapeutic options. Clin. Infect. Dis. 2009 48 3 328 337 10.1086/695852 19123868
    [Google Scholar]
  2. Rb-Silva R. Goios A. Kelly C. Teixeira P. João C. Horta A. Correia-Neves M. Definition of immunological nonresponse to antiretroviral therapy: A systematic review. J. Acquir. Immune Defic. Syndr. 2019 82 5 452 461 10.1097/QAI.0000000000002157 31592836
    [Google Scholar]
  3. Phillips A.N. Gazzard B. Gilson R. Easterbrook P. Johnson M. Walsh J. Leen C. Fisher M. Orkin C. Anderson J. Pillay D. Delpech V. Sabin C. Schwenk A. Dunn D. Gompels M. Hill T. Porter K. Babiker A. Rate of AIDS diseases or death in HIV-infected antiretroviral therapy-naive individuals with high CD4 cell count. AIDS 2007 21 13 1717 1721 10.1097/QAD.0b013e32827038bf 17690569
    [Google Scholar]
  4. Guiguet M. Boué F. Cadranel J. Lang J.M. Rosenthal E. Costagliola D. Effect of immunodeficiency, HIV viral load, and antiretroviral therapy on the risk of individual malignancies (FHDH-ANRS CO4): A prospective cohort study. Lancet Oncol. 2009 10 12 1152 1159 10.1016/S1470‑2045(09)70282‑7 19818686
    [Google Scholar]
  5. Mocroft A. Reiss P. Gasiorowski J. Ledergerber B. Kowalska J. Chiesi A. Gatell J. Rakhmanova A. Johnson M. Kirk O. Lundgren J. EuroSIDA Study Group Serious fatal and nonfatal non-AIDS-defining illnesses in Europe. J. Acquir. Immune Defic. Syndr. 2010 55 2 262 270 10.1097/QAI.0b013e3181e9be6b 20700060
    [Google Scholar]
  6. Viard J.P. Mocroft A. Chiesi A. Kirk O. Røge B. Panos G. Vetter N. Bruun J.N. Johnson M. Lundgren J.D. Influence of age on CD4 cell recovery in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy: Evidence from the EuroSIDA study. J. Infect. Dis. 2001 183 8 1290 1294 10.1086/319678 11262215
    [Google Scholar]
  7. Shukla S. Kumari S. Bal S.K. Monaco D.C. Ribeiro S.P. Sekaly R.P. Sharma A.A. “Go”, “No Go,” or “Where to Go”; does microbiota dictate T cell exhaustion, programming, and HIV persistence? Curr. Opin. HIV AIDS 2021 16 4 215 222 10.1097/COH.0000000000000692 34039845
    [Google Scholar]
  8. Ferrari B. Da Silva A.C. Liu K.H. Saidakova E.V. Korolevskaya L.B. Shmagel K.V. Shive C. Pacheco Sanchez G. Retuerto M. Sharma A.A. Ghneim K. Noel-Romas L. Rodriguez B. Ghannoum M.A. Hunt P.P. Deeks S.G. Burgener A.D. Jones D.P. Dobre M.A. Marconi V.C. Sekaly R.P. Younes S.A. Gut-derived bacterial toxins impair memory CD4+ T cell mitochondrial function in HIV-1 infection. J. Clin. Invest. 2022 132 9 e149571 10.1172/JCI149571 35316209
    [Google Scholar]
  9. Younes S.A. Yassine-Diab B. Dumont A.R. Boulassel M.R. Grossman Z. Routy J.P. Sékaly R.P. HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity. J. Exp. Med. 2003 198 12 1909 1922 10.1084/jem.20031598 14676302
    [Google Scholar]
  10. Yang X. Su B. Zhang X. Liu Y. Wu H. Zhang T. Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders. J. Leukoc. Biol. 2020 107 4 597 612 10.1002/JLB.4MR1019‑189R 31965635
    [Google Scholar]
  11. Carvalho-Silva W.H.V. Andrade-Santos J.L. Souto F.O. Coelho A.V.C. Crovella S. Guimarães R.L. Immunological recovery failure in cART-treated HIV-positive patients is associated with reduced thymic output and RTE CD4+ T cell death by pyroptosis. J. Leukoc. Biol. 2020 107 1 85 94 10.1002/JLB.4A0919‑235R 31691351
    [Google Scholar]
  12. Petitjean G. Chevalier M.F. Tibaoui F. Didier C. Manea M.E. Liovat A.S. Campa P. Müller-Trutwin M. Girard P.M. Meyer L. Barré-Sinoussi F. Scott-Algara D. Weiss L. Level of double negative T cells, which produce TGF-β and IL-10, predicts CD8 T-cell activation in primary HIV-1 infection. AIDS 2012 26 2 139 148 10.1097/QAD.0b013e32834e1484 22045342
    [Google Scholar]
  13. Bentwich Z. Kalinkovich A. Weisman Z. Grossman Z. Immune activation in the context of HIV infection. Clin. Exp. Immunol. 2001 111 1 1 2 10.1046/j.1365‑2249.1998.00483.x 9472654
    [Google Scholar]
  14. Hazenberg M.D. Otto S.A. van Benthem B.H.B. Roos M.T. Coutinho R.A. Lange J.M.A. Hamann D. Prins M. Miedema F. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS 2003 17 13 1881 1888 10.1097/00002030‑200309050‑00006 12960820
    [Google Scholar]
  15. Milush J.M. Mir K.D. Sundaravaradan V. Gordon S.N. Engram J. Cano C.A. Reeves J.D. Anton E. O’Neill E. Butler E. Hancock K. Cole K.S. Brenchley J.M. Else J.G. Silvestri G. Sodora D.L. Lack of clinical AIDS in SIV-infected sooty mangabeys with significant CD4+ T cell loss is associated with double-negative T cells. J. Clin. Invest. 2011 121 3 1102 1110 10.1172/JCI44876 21317533
    [Google Scholar]
  16. Giorgi J.V. Hultin L.E. McKeating J.A. Johnson T.D. Owens B. Jacobson L.P. Shih R. Lewis J. Wiley D.J. Phair J.P. Wolinsky S.M. Detels R. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J. Infect. Dis. 1999 179 4 859 870 10.1086/314660 10068581
    [Google Scholar]
  17. Deeks S.G. Kitchen C.M.R. Liu L. Guo H. Gascon R. Narváez A.B. Hunt P. Martin J.N. Kahn J.O. Levy J. McGrath M.S. Hecht F.M. Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 2004 104 4 942 947 10.1182/blood‑2003‑09‑3333 15117761
    [Google Scholar]
  18. Liu Z. Cumberland W.G. Hultin L.E. Prince H.E. Detels R. Giorgi J.V. Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. 1997 16 2 83 92 10.1097/00042560‑199710010‑00003 9358102
    [Google Scholar]
  19. Brenchley J.M. Price D.A. Schacker T.W. Asher T.E. Silvestri G. Rao S. Kazzaz Z. Bornstein E. Lambotte O. Altmann D. Blazar B.R. Rodriguez B. Teixeira-Johnson L. Landay A. Martin J.N. Hecht F.M. Picker L.J. Lederman M.M. Deeks S.G. Douek D.C. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat. Med. 2006 12 12 1365 1371 10.1038/nm1511 17115046
    [Google Scholar]
  20. Schindler M. Münch J. Kutsch O. Li H. Santiago M.L. Bibollet-Ruche F. Müller-Trutwin M.C. Novembre F.J. Peeters M. Courgnaud V. Bailes E. Roques P. Sodora D.L. Silvestri G. Sharp P.M. Hahn B.H. Kirchhoff F. Nef-mediated suppression of T cell activation was lost in a lentiviral lineage that gave rise to HIV-1. Cell 2006 125 6 1055 1067 10.1016/j.cell.2006.04.033 16777597
    [Google Scholar]
  21. Smed-Sörensen A. Loré K. Vasudevan J. Louder M.K. Andersson J. Mascola J.R. Spetz A.L. Koup R.A. Differential susceptibility to human immunodeficiency virus type 1 infection of myeloid and plasmacytoid dendritic cells. J. Virol. 2005 79 14 8861 8869 10.1128/JVI.79.14.8861‑8869.2005 15994779
    [Google Scholar]
  22. Eggena M.P. Barugahare B. Jones N. Okello M. Mutalya S. Kityo C. Mugyenyi P. Cao H. Depletion of regulatory T cells in HIV infection is associated with immune activation. J. Immunol. 2005 174 7 4407 4414 10.4049/jimmunol.174.7.4407 15778406
    [Google Scholar]
  23. Guo Y. Zhang Y.L. Zhu D. Gong F.H. Gao Y.S. Zhu K.R. Li S.S. Abnormal Activation of T Cells in HIV-1 Infection After Antiretroviral Therapy. Sichuan Da Xue Xue Bao Yi Xue Ban 2023 54 2 415 421 36949708
    [Google Scholar]
  24. Wu Z. Zheng Y. Sheng J. Han Y. Yang Y. Pan H. Yao J. CD3+CD4-CD8- (double-negative) T cells in inflammation, immune disorders and cancer. Front. Immunol. 2022 13 816005 10.3389/fimmu.2022.816005 35222392
    [Google Scholar]
  25. Fischer K. Voelkl S. Heymann J. Przybylski G.K. Mondal K. Laumer M. Kunz-Schughart L. Schmidt C.A. Andreesen R. Mackensen A. Isolation and characterization of human antigen-specific TCRαβ+ CD4-CD8- double-negative regulatory T cells. Blood 2005 105 7 2828 2835 10.1182/blood‑2004‑07‑2583 15572590
    [Google Scholar]
  26. Paul S. Shilpi Lal G. Role of gamma-delta ( γδ ) T cells in autoimmunity. J. Leukoc. Biol. 2015 97 2 259 271 10.1189/jlb.3RU0914‑443R 25502468
    [Google Scholar]
  27. Crispín J.C. Tsokos G.C. Human TCR-alpha beta+ CD4- CD8- T cells can derive from CD8+ T cells and display an inflammatory effector phenotype. J. Immunol. 2009 183 7 4675 4681 10.4049/jimmunol.0901533 19734235
    [Google Scholar]
  28. Rensing-Ehl A. Völkl S. Speckmann C. Lorenz M.R. Ritter J. Janda A. Abinun M. Pircher H. Bengsch B. Thimme R. Fuchs I. Ammann S. Allgäuer A. Kentouche K. Cant A. Hambleton S. Bettoni da Cunha C. Huetker S. Kühnle I. Pekrun A. Seidel M.G. Hummel M. Mackensen A. Schwarz K. Ehl S. Abnormally differentiated CD4+ or CD8+ T cells with phenotypic and genetic features of double negative T cells in human Fas deficiency. Blood 2014 124 6 851 860 10.1182/blood‑2014‑03‑564286 24894771
    [Google Scholar]
  29. Zhang D. Yang W. Degauque N. Tian Y. Mikita A. Zheng X.X. New differentiation pathway for double-negative regulatory T cells that regulates the magnitude of immune responses. Blood 2007 109 9 4071 4079 10.1182/blood‑2006‑10‑050625 17197428
    [Google Scholar]
  30. Chen W. Diao J. Stepkowski S.M. Zhang L. Both infiltrating regulatory T cells and insufficient antigen presentation are involved in long-term cardiac xenograft survival. J. Immunol. 2007 179 3 1542 1548 10.4049/jimmunol.179.3.1542 17641020
    [Google Scholar]
  31. Zhang D. Zhang W. Ng T.W. Wang Y. Liu Q. Gorantla V. Lakkis F. Zheng X.X. Adoptive cell therapy using antigen-specific CD4−CD8− T regulatory cells to prevent autoimmune diabetes and promote islet allograft survival in NOD mice. Diabetologia 2011 54 8 2082 2092 10.1007/s00125‑011‑2179‑4 21594554
    [Google Scholar]
  32. Maccari M.E. Fuchs S. Kury P. Andrieux G. Völkl S. Bengsch B. Lorenz M.R. Heeg M. Rohr J. Jägle S. Castro C.N. Groß M. Warthorst U. König C. Fuchs I. Speckmann C. Thalhammer J. Kapp F.G. Seidel M.G. Dückers G. Schönberger S. Schütz C. Führer M. Kobbe R. Holzinger D. Klemann C. Smisek P. Owens S. Horneff G. Kolb R. Naumann-Bartsch N. Miano M. Staniek J. Rizzi M. Kalina T. Schneider P. Erxleben A. Backofen R. Ekici A. Niemeyer C.M. Warnatz K. Grimbacher B. Eibel H. Mackensen A. Frei A.P. Schwarz K. Boerries M. Ehl S. Rensing-Ehl A. A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS. J. Exp. Med. 2021 218 2 e20192191 10.1084/jem.20192191 33170215
    [Google Scholar]
  33. Zhang Z.X. Ma Y. Wang H. Arp J. Jiang J. Huang X. He K.M. Garcia B. Madrenas J. Zhong R. Double-negative T cells, activated by xenoantigen, lyse autologous B and T cells using a perforin/granzyme-dependent, Fas-Fas ligand-independent pathway. J. Immunol. 2006 177 10 6920 6929 10.4049/jimmunol.177.10.6920 17082607
    [Google Scholar]
  34. Li W. Tian Y. Li Z. Gao J. Shi W. Zhu J. Zhang D. Ex vivo converted double negative T cells suppress activated B cells. Int. Immunopharmacol. 2014 20 1 164 169 10.1016/j.intimp.2014.02.034 24613134
    [Google Scholar]
  35. Gao J.F. McIntyre M.S.F. Juvet S.C. Diao J. Li X. Vanama R.B. Mak T.W. Cattral M.S. Zhang L. Regulation of antigen-expressing dendritic cells by double negative regulatory T cells. Eur. J. Immunol. 2011 41 9 2699 2708 10.1002/eji.201141428 21660936
    [Google Scholar]
  36. Su Y. Huang X. Wang S. Min W.P. Yin Z. Jevnikar A.M. Zhang Z.X. Double negative T reg cells promote nonmyeloablative bone marrow chimerism by inducing T -cell clonal deletion and suppressing NK cell function. Eur. J. Immunol. 2012 42 5 1216 1225 10.1002/eji.201141808 22539294
    [Google Scholar]
  37. Young K.J. DuTemple B. Phillips M.J. Zhang L. Inhibition of graft-versus-host disease by double-negative regulatory T cells. J. Immunol. 2003 171 1 134 141 10.4049/jimmunol.171.1.134 12816991
    [Google Scholar]
  38. Yang L. Zhu Y. Tian D. Wang S. Guo J. Sun G. Jin H. Zhang C. Shi W. Gershwin M.E. Zhang Z. Zhao Y. Zhang D. Transcriptome landscape of double negative T cells by single-cell RNA sequencing. J. Autoimmun. 2021 121 102653 10.1016/j.jaut.2021.102653 34022742
    [Google Scholar]
  39. Zhang Z.X. Yang L. Young K.J. DuTemple B. Zhang L. Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nat. Med. 2000 6 7 782 789 10.1038/77513 10888927
    [Google Scholar]
  40. Young K.J. Zhang L. The nature and mechanisms of DN regulatory T-Cell mediated suppression. Hum. Immunol. 2002 63 10 926 934 10.1016/S0198‑8859(02)00446‑9 12368045
    [Google Scholar]
  41. Vinton C. Klatt N.R. Harris L.D. Briant J.A. Sanders-Beer B.E. Herbert R. Woodward R. Silvestri G. Pandrea I. Apetrei C. Hirsch V.M. Brenchley J.M. CD4-like immunological function by CD4- T cells in multiple natural hosts of simian immunodeficiency virus. J. Virol. 2011 85 17 8702 8708 10.1128/JVI.00332‑11 21715501
    [Google Scholar]
  42. Crispín J.C. Oukka M. Bayliss G. Cohen R.A. Van Beek C.A. Stillman I.E. Kyttaris V.C. Juang Y.T. Tsokos G.C. Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys. J. Immunol. 2008 181 12 8761 8766 10.4049/jimmunol.181.12.8761 19050297
    [Google Scholar]
  43. Fang L. Ly D. Wang S. Lee J.B. Kang H. Xu H. Yao J. Tsao M. Liu W. Zhang L. Targeting late-stage non-small cell lung cancer with a combination of DNT cellular therapy and PD-1 checkpoint blockade. J. Exp. Clin. Cancer Res. 2019 38 1 123 10.1186/s13046‑019‑1126‑y 30857561
    [Google Scholar]
  44. Merims S. Li X. Joe B. Dokouhaki P. Han M. Childs R.W. Wang Z-Y. Gupta V. Minden M.D. Zhang L. Anti-leukemia effect of ex vivo expanded DNT cells from AML patients: A potential novel autologous T-cell adoptive immunotherapy. Leukemia 2011 25 9 1415 1422 10.1038/leu.2011.99 21566657
    [Google Scholar]
  45. Liang Q. Jiao Y. Zhang T. Wang R. Li W. Zhang H. Huang X. Tang Z. Wu H. Double Negative (DN) [CD3(+)CD4(−)CD8(−)] T cells correlate with disease progression during HIV infection. Immunol. Invest. 2013 42 5 431 437 10.3109/08820139.2013.805763 23802173
    [Google Scholar]
  46. Lu X. Su B. Xia H. Zhang X. Liu Z. Ji Y. Yang Z. Dai L. Mayr L.M. Moog C. Wu H. Huang X. Zhang T. Low double-negative CD3+CD4−CD8− T cells are associated with incomplete restoration of CD4+ T cells and higher immune activation in HIV-1 immunological non-responders. Front. Immunol. 2016 7 579 10.3389/fimmu.2016.00579 28018346
    [Google Scholar]
  47. Gan B. Mitochondrial regulation of ferroptosis. J. Cell Biol. 2021 220 9 e202105043 10.1083/jcb.202105043 34328510
    [Google Scholar]
  48. Blas-Garcia A. Apostolova N. Esplugues J.V. Oxidative stress and mitochondrial impairment after treatment with anti-HIV drugs: Clinical implications. Curr. Pharm. Des. 2011 17 36 4076 4086 10.2174/138161211798764951 22188456
    [Google Scholar]
  49. Xiao Q. Yan L. Han J. Yang S. Tang Y. Li Q. Lao X. Chen Z. Xiao J. Zhao H. Yu F. Zhang F. Metabolism-dependent ferroptosis promotes mitochondrial dysfunction and inflammation in CD4+ T lymphocytes in HIV-infected immune non-responders. EBioMedicine 2022 86 104382 10.1016/j.ebiom.2022.104382 36462403
    [Google Scholar]
  50. Benveniste O. Flahault A. Rollot F. Elbim C. Estaquier J. Pédron B. Duval X. Dereuddre-Bosquet N. Clayette P. Sterkers G. Simon A. Ameisen J.C. Leport C. Mechanisms involved in the low-level regeneration of CD4+ cells in HIV-1-infected patients receiving highly active antiretroviral therapy who have prolonged undetectable plasma viral loads. J. Infect. Dis. 2005 191 10 1670 1679 10.1086/429670 15838794
    [Google Scholar]
  51. Moses A. Nelson J. Bagby G.C. Jr The influence of human immunodeficiency virus-1 on hematopoiesis. Blood 1998 91 5 1479 1495 10.1182/blood.V91.5.1479 9473211
    [Google Scholar]
  52. Isgrò A. Aiuti A. Mezzaroma I. Addesso M. Riva E. Giovannetti A. Mazzetta F. Alario C. Mazzone A. Ruco L. Aiuti F. Improvement of interleukin 2 production, clonogenic capability and restoration of stromal cell function in human immunodeficiency virus-type-1 patients after highly active antiretroviral therapy. Br. J. Haematol. 2002 118 3 864 874 10.1046/j.1365‑2141.2002.03680.x 12181060
    [Google Scholar]
  53. Isgrò A. Aiuti A. Leti W. Gramiccioni C. Esposito A. Mezzaroma I. Aiuti F. Immunodysregulation of HIV disease at bone marrow level. Autoimmun. Rev. 2005 4 8 486 490 10.1016/j.autrev.2005.04.014 16214083
    [Google Scholar]
  54. Aiuti F. Mezzaroma I. Failure to reconstitute CD4+ T-cells despite suppression of HIV replication under HAART. AIDS Rev. 2006 8 2 88 97 16848276
    [Google Scholar]
  55. Isgrò A. Leti W. De Santis W. Marziali M. Esposito A. Fimiani C. Luzi G. Pinti M. Cossarizza A. Aiuti F. Mezzaroma I. Altered clonogenic capability and stromal cell function characterize bone marrow of HIV-infected subjects with low CD4+ T cell counts despite viral suppression during HAART. Clin. Infect. Dis. 2008 46 12 1902 1910 10.1086/588480 18462177
    [Google Scholar]
  56. Badolato R. Immunological nonresponse to highly active antiretroviral therapy in HIV-infected subjects: Is the bone marrow impairment causing CD4 lymphopenia? Clin. Infect. Dis. 2008 46 12 1911 1912 10.1086/588481 18462176
    [Google Scholar]
  57. Kolte L. Dreves A.M. Ersbøll A.K. Strandberg C. Jeppesen D.L. Nielsen J.O. Ryder L.P. Nielsen S.D. Association between larger thymic size and higher thymic output in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy. J. Infect. Dis. 2002 185 11 1578 1585 10.1086/340418 12023763
    [Google Scholar]
  58. Franco J.M. Rubio A. Martínez-Moya M. Leal M. Merchante E. Sánchez-Quijano A. Lissen E. T-cell repopulation and thymic volume in HIV-1–infected adult patients after highly active antiretroviral therapy. Blood 2002 99 10 3702 3706 10.1182/blood.V99.10.3702 11986226
    [Google Scholar]
  59. Fry T.J. Mackall C.L. What limits immune reconstitution in HIV infection? Divergent tools converge on thymic function. AIDS 2001 15 14 1881 1882 10.1097/00002030‑200109280‑00019 11579252
    [Google Scholar]
  60. Douek D.C. McFarland R.D. Keiser P.H. Gage E.A. Massey J.M. Haynes B.F. Polis M.A. Haase A.T. Feinberg M.B. Sullivan J.L. Jamieson B.D. Zack J.A. Picker L.J. Koup R.A. Changes in thymic function with age and during the treatment of HIV infection. Nature 1998 396 6712 690 695 10.1038/25374 9872319
    [Google Scholar]
  61. Teixeira L. Valdez H. McCune J.M. Koup R.A. Badley A.D. Hellerstein M.K. Napolitano L.A. Douek D.C. Mbisa G. Deeks S. Harris J.M. Barbour J.D. Gross B.H. Francis I.R. Halvorsen R. Asaad R. Lederman M.M. Poor CD4 T cell restoration after suppression of HIV-1 replication may reflect lower thymic function. AIDS 2001 15 14 1749 1756 10.1097/00002030‑200109280‑00002 11579235
    [Google Scholar]
  62. Marziali M. De Santis W. Carello R. Leti W. Esposito A. Isgrò A. Fimiani C. Sirianni M.C. Mezzaroma I. Aiuti F. T-cell homeostasis alteration in HIV-1 infected subjects with low CD4 T-cell count despite undetectable virus load during HAART. AIDS 2006 20 16 2033 2041 10.1097/01.aids.0000247588.69438.fd 17053349
    [Google Scholar]
  63. Marchetti G. Gori A. Casabianca A. Magnani M. Franzetti F. Clerici M. Perno C.F. Monforte A.A. Galli M. Meroni L. Comparative analysis of T-cell turnover and homeostatic parameters in HIV-infected patients with discordant immune-virological responses to HAART. AIDS 2006 20 13 1727 1736 10.1097/01.aids.0000242819.72839.db 16931937
    [Google Scholar]
  64. Valdez H. Connick E. Smith K.Y. Lederman M.M. Bosch R.J. Kim R.S. St Clair M. Kuritzkes D.R. Kessler H. Fox L. Blanchard-Vargas M. Landay A. Limited immune restoration after 3 years’ suppression of HIV-1 replication in patients with moderately advanced disease. AIDS 2002 16 14 1859 1866 10.1097/00002030‑200209270‑00002 12351945
    [Google Scholar]
  65. Hunt P.W. Martin J.N. Sinclair E. Bredt B. Hagos E. Lampiris H. Deeks S.G. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J. Infect. Dis. 2003 187 10 1534 1543 10.1086/374786 12721933
    [Google Scholar]
  66. Dixon S.J. Olzmann J.A. The cell biology of ferroptosis. Nat. Rev. Mol. Cell Biol. 2024 25 6 424 442 10.1038/s41580‑024‑00703‑5 38366038
    [Google Scholar]
  67. Feng H. Stockwell B.R. Unsolved mysteries: How does lipid peroxidation cause ferroptosis? PLoS Biol. 2018 16 5 e2006203 10.1371/journal.pbio.2006203 29795546
    [Google Scholar]
  68. Battaglia A.M. Chirillo R. Aversa I. Sacco A. Costanzo F. Biamonte F. Ferroptosis and cancer: Mitochondria meet the “iron maiden” cell death. Cells 2020 9 6 1505 10.3390/cells9061505 32575749
    [Google Scholar]
  69. Li Y. Ran Q. Duan Q. Jin J. Wang Y. Yu L. Wang C. Zhu Z. Chen X. Weng L. Li Z. Wang J. Wu Q. Wang H. Tian H. Song S. Shan Z. Zhai Q. Qin H. Chen S. Fang L. Yin H. Zhou H. Jiang X. Wang P. 7-Dehydrocholesterol dictates ferroptosis sensitivity. Nature 2024 626 7998 411 418 10.1038/s41586‑023‑06983‑9 38297130
    [Google Scholar]
  70. Gao M. Yi J. Zhu J. Minikes A.M. Monian P. Thompson C.B. Jiang X. Role of mitochondria in ferroptosis. Mol. Cell 2019 73 2 354 363.e3 10.1016/j.molcel.2018.10.042 30581146
    [Google Scholar]
  71. Velikkakam T. Gollob K.J. Dutra W.O. Double-negative T cells: Setting the stage for disease control or progression. Immunology 2022 165 4 371 385 10.1111/imm.13441 34939192
    [Google Scholar]
  72. Sundaravaradan V. Mir K.D. Sodora D.L. Double-negative T cells during HIV/SIV infections. Curr. Opin. HIV AIDS 2012 7 2 164 171 10.1097/COH.0b013e3283504a66 22241163
    [Google Scholar]
  73. Hu Z. Yang M. Chen H. He C. Lin Z. Yang X. Li H. Shen W. Lu D. Xu X. Double-negative T cells: A promising avenue of adoptive cell therapy in transplant oncology. J. Zhejiang Univ. Sci. B 2023 24 5 387 396 10.1631/jzus.B2200528 37190888
    [Google Scholar]
  74. Stockwell B.R. Friedmann Angeli J.P. Bayir H. Bush A.I. Conrad M. Dixon S.J. Fulda S. Gascón S. Hatzios S.K. Kagan V.E. Noel K. Jiang X. Linkermann A. Murphy M.E. Overholtzer M. Oyagi A. Pagnussat G.C. Park J. Ran Q. Rosenfeld C.S. Salnikow K. Tang D. Torti F.M. Torti S.V. Toyokuni S. Woerpel K.A. Zhang D.D. Ferroptosis: A regulated cell death nexus linking metabolism, redox biology, and disease. Cell 2017 171 2 273 285 10.1016/j.cell.2017.09.021 28985560
    [Google Scholar]
  75. Angeli J.P.F. Shah R. Pratt D.A. Conrad M. Ferroptosis inhibition: Mechanisms and opportunities. Trends Pharmacol. Sci. 2017 38 5 489 498 10.1016/j.tips.2017.02.005 28363764
    [Google Scholar]
  76. Abrams R.P. Carroll W.L. Woerpel K.A. Five-membered ring peroxide selectively initiates ferroptosis in cancer cells. ACS Chem. Biol. 2016 11 5 1305 1312 10.1021/acschembio.5b00900 26797166
    [Google Scholar]
  77. Yagoda N. von Rechenberg M. Zaganjor E. Bauer A.J. Yang W.S. Fridman D.J. Wolpaw A.J. Smukste I. Peltier J.M. Boniface J.J. Smith R. Lessnick S.L. Sahasrabudhe S. Stockwell B.R. RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 2007 447 7146 865 869 10.1038/nature05859 17568748
    [Google Scholar]
  78. Dolma S. Lessnick S.L. Hahn W.C. Stockwell B.R. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 2003 3 3 285 296 10.1016/S1535‑6108(03)00050‑3 12676586
    [Google Scholar]
  79. Friedmann Angeli J.P. Schneider M. Proneth B. Tyurina Y.Y. Tyurin V.A. Hammond V.J. Herbach N. Aichler M. Walch A. Eggenhofer E. Basavarajappa D. Rådmark O. Kobayashi S. Seibt T. Beck H. Neff F. Esposito I. Wanke R. Förster H. Yefremova O. Heinrichmeyer M. Bornkamm G.W. Geissler E.K. Thomas S.B. Stockwell B.R. O’Donnell V.B. Kagan V.E. Schick J.A. Conrad M. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 2014 16 12 1180 1191 10.1038/ncb3064 25402683
    [Google Scholar]
  80. Liu Y. Lu S. Wu L. Yang L. Yang L. Wang J. The diversified role of mitochondria in ferroptosis in cancer. Cell Death Dis. 2023 14 8 519 10.1038/s41419‑023‑06045‑y 37580393
    [Google Scholar]
/content/journals/chr/10.2174/011570162X366300250509112302
Loading
Ferroptosis and Dysfunction of CD3+CD4−CD8− T Cells are Associated with Poor Immune Reconstitution in HIV Patients
Bentham Science Publishers ; https://doi.org/10.2174/011570162X366300250509112302
/content/journals/chr/10.2174/011570162X366300250509112302
/content/journals/chr/10.2174/011570162X366300250509112302
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: Ferroptosis ; double-negative T cell ; Immune non-responder (INR) ; immune reconstitution ; functional impairment ; Human immunodeficiency virus (HIV)

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test