Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

Xiaodong Yang, Bin Su, Xin Zhang, Yan Liu, Hao Wu, Tong Zhang, Xiaodong Yang, Bin Su, Xin Zhang, Yan Liu, Hao Wu, Tong Zhang

Abstract

The morbidity and mortality of HIV type-1 (HIV-1)-related diseases were dramatically diminished by the grounds of the introduction of potent antiretroviral therapy, which induces persistent suppression of HIV-1 replication and gradual recovery of CD4+ T-cell counts. However, ∼10-40% of HIV-1-infected individuals fail to achieve normalization of CD4+ T-cell counts despite persistent virological suppression. These patients are referred to as "inadequate immunological responders," "immunodiscordant responders," or "immunological non-responders (INRs)" who show severe immunological dysfunction. Indeed, INRs are at an increased risk of clinical progression to AIDS and non-AIDS events and present higher rates of mortality than HIV-1-infected individuals with adequate immune reconstitution. To date, the underlying mechanism of incomplete immune reconstitution in HIV-1-infected patients has not been fully elucidated. In light of this limitation, it is of substantial practical significance to deeply understand the mechanism of immune reconstitution and design effective individualized treatment strategies. Therefore, in this review, we aim to highlight the mechanism and risk factors of incomplete immune reconstitution and strategies to intervene.

Keywords: CD4+ T cells; HIV-1 infection; antiretroviral therapy; immune reconstitution; immunological non-responders.

Conflict of interest statement

The authors declare no conflicts of interest.

© 2020 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals, Inc. on behalf of Society for Leukocyte Biology.

Figures

Figure 1
Figure 1
Factors associated with immunological non‐responders. Current understanding of the mechanism of incomplete immune reconstitution. INRs show severe immune dysfunction, including reduced production of progenitor cells in the bone marrow; thymic dysfunction; reduced CD34+ hematopoietic progenitor cells; abnormal immune activation; immune exhaustion; immunoregulatory cell imbalance, such as Treg and Th17 cells; increased immune‐senescence and cell apoptosis/pyroptosis, lymphoid tissue fibrosis, and microbial translocation; and persistent viral replication due to the HIV reservoir, and so on. Arrows in red highlight the maturation route of CD4+ T cells, while arrows in black indicate the factors associated with incomplete immune reconstitution. Th: helper T cell; Treg: regulatory T cell; NK: natural killer

References

    1. Lucas S, Nelson AM. HIV and the spectrum of human disease. J Pathol. 2015;235:229‐241.
    1. Ghosn J, Taiwo B, Seedat S, et al. Hiv. Lancet. 2018;392:685‐697.
    1. Saag MS, Benson CA, Gandhi RT, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2018 recommendations of the International Antiviral Society‐USA panel. JAMA. 2018;320(4):379‐396.
    1. Prabhu S, Harwell JI, Kumarasamy N. Advanced HIV: diagnosis, treatment, and prevention. Lancet HIV. 2019;6:PE540‐PE551.
    1. Battegay M, Nuesch R, Hirschel B, et al. Immunological recovery and antiretroviral therapy in HIV‐1 infection. Lancet Infect Dis. 2006;6:280‐287.
    1. Corbeau P, Reynes J. Immune reconstitution under antiretroviral therapy: the new challenge in HIV‐1 infection. Blood. 2011;117:5582‐5590.
    1. Gazzola L, Tincati C, Bellistri GM, et al. 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;48:328‐337.
    1. Young J, Psichogiou M, Ayayi S, et al Opportunistic Infections Project Team of the Collaboration of Observational HIVERiEiE . CD4 cell count and the risk of AIDS or death in HIV‐Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE. PLoS Med. 2012;9:e1001194.
    1. Baker JV, Peng G, Rapkin J, et al. Poor initial CD4+ recovery with antiretroviral therapy prolongs immune depletion and increases risk for AIDS and non‐AIDS diseases. J Acquir Immune Defic Syndr. 2008;48:541‐546.
    1. Pacheco YM, Jarrin I, Rosado I, et al. Increased risk of non‐AIDS‐related events in HIV subjects with persistent low CD4 counts despite cART in the CoRIS cohort. Antiviral Res. 2015;117:69‐74.
    1. Engsig FN, Zangerle R, Katsarou O, et al. Long‐term mortality in HIV‐positive individuals virally suppressed for >3 years with incomplete CD4 recovery. Clin Infect Dis. 2014;58:1312‐1321.
    1. Takuva S, Maskew M, Brennan AT, et al. Poor CD4 recovery and risk of subsequent progression to AIDS or death despite viral suppression in a South African cohort. J Int AIDS Soc. 2014;17:18651.
    1. van Lelyveld SF, Gras L, Kesselring A, et al. Long‐term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort. AIDS. 2012;26:465‐474.
    1. Massanella M, Negredo E, Clotet B, et al. Immunodiscordant responses to HAART–mechanisms and consequences. Expert Rev Clin Immunol. 2013;9:1135‐1149.
    1. Nakanjako D, Kiragga AN, Musick BS, et al. Frequency and impact of suboptimal immune recovery on first‐line antiretroviral therapy within the international epidemiologic databases to evaluate AIDS in East Africa. AIDS. 2016;30:1913‐1922.
    1. Kaufmann GR, Furrer H, Ledergerber B, et al. Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/microL in HIV type 1‐infected individuals receiving potent antiretroviral therapy. Clin Infect Dis. 2005;41:361‐372.
    1. Lewden C, Chene G, Morlat P, et al. HIV‐infected adults with a CD4 cell count greater than 500 cells/mm3 on long‐term combination antiretroviral therapy reach same mortality rates as the general population. J Acquir Immune Defic Syndr. 2007;46:72‐77.
    1. Kroeze S, Ondoa P, Kityo CM, et al. Suboptimal immune recovery during antiretroviral therapy with sustained HIV suppression in sub‐Saharan Africa. AIDS. 2018;32:1043‐1051.
    1. Panel on Antiretroviral Guidelines for Adults and Adolescents . Guidelines for the use of antiretroviral agents in HIV‐1 infected adults and adolescents. Washington, DC: Department of Health and Human Services, 2008.
    1. Lu W, Mehraj V, Vyboh K, et al. CD4:CD8 ratio as a frontier marker for clinical outcome, immune dysfunction and viral reservoir size in virologically suppressed HIV‐positive patients. J Int AIDS Soc. 2015;18:20052.
    1. Serrano‐Villar S, Sainz T, Lee SA, et al. HIV‐infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non‐AIDS morbidity and mortality. PLoS Pathog. 2014;10:e1004078.
    1. Buggert M, Frederiksen J, Noyan K, et al. Multiparametric bioinformatics distinguish the CD4/CD8 ratio as a suitable laboratory predictor of combined T cell pathogenesis in HIV infection. J Immunol. 2014;192:2099‐2108.
    1. Rodriguez‐Gallego E, Gomez J, Pacheco YM, et al. A baseline metabolomic signature is associated with immunological CD4+ T‐cell recovery after 36 months of antiretroviral therapy in HIV‐infected patients. AIDS. 2018;32:565‐573.
    1. Gunda DW, Kilonzo SB, Kamugisha E, et al. Prevalence and risk factors of poor immune recovery among adult HIV patients attending care and treatment centre in northwestern Tanzania following the use of highly active antiretroviral therapy: a retrospective study. BMC Res Notes. 2017;10:197.
    1. Utay NS, Hunt PW. Role of immune activation in progression to AIDS. Curr Opin HIV AIDS. 2016;11:131‐137.
    1. Gaardbo JC, Hartling HJ, Gerstoft J, et al. Incomplete immune recovery in HIV infection: mechanisms, relevance for clinical care, and possible solutions. Clin Dev Immunol. 2012;2012:670957.
    1. Spits H, Blom B, Jaleco AC, et al. Early stages in the development of human T, natural killer and thymic dendritic cells. Immunol Rev. 1998;165:75‐86.
    1. Chelucci C, Casella I, Federico M, et al. Lineage‐specific expression of human immunodeficiency virus (HIV) receptor/coreceptors in differentiating hematopoietic precursors: correlation with susceptibility to T‐ and M‐tropic HIV and chemokine‐mediated HIV resistance. Blood. 1999;94:1590‐1600.
    1. Chelucci C, Hassan HJ, Locardi C, et al. In vitro human immunodeficiency virus‐1 infection of purified hematopoietic progenitors in single‐cell culture. Blood. 1995;85:1181‐1187.
    1. Nixon CC, Vatakis DN, Reichelderfer SN, et al. HIV‐1 infection of hematopoietic progenitor cells in vivo in humanized mice. Blood. 2013;122:2195‐2204.
    1. Carter CC, Onafuwa‐Nuga A, McNamara LA, et al. HIV‐1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nat Med. 2010;16:446‐451.
    1. McNamara LA, Collins KL. Hematopoietic stem/precursor cells as HIV reservoirs. Curr Opin HIV AIDS. 2011;6:43‐48.
    1. Tsukamoto T. HIV impacts CD34(+) progenitors involved in T‐cell differentiation during coculture with mouse stromal OP9‐DL1 cells. Front Immunol. 2019;10:81.
    1. Li G, Zhao J, Cheng L, et al. HIV‐1 infection depletes human CD34+CD38‐ hematopoietic progenitor cells via pDC‐dependent mechanisms. PLoS Pathog. 2017;13:e1006505.
    1. Isgro A, Leti W, De Santis W, et al. 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;46:1902‐1910.
    1. Sauce D, Larsen M, Fastenackels S, et al. HIV disease progression despite suppression of viral replication is associated with exhaustion of lymphopoiesis. Blood. 2011;117:5142‐5151.
    1. Menkova‐Garnier I, Hocini H, Foucat E, et al. P2X7 receptor inhibition improves CD34 T‐cell differentiation in HIV‐infected immunological nonresponders on c‐ART. PLoS Pathog. 2016;12:e1005571.
    1. Mariathasan S, Weiss DS, Newton K, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440(7081):228‐232.
    1. Guo X, He S, Lv X, et al. The role of HIV‐1 in affecting the proliferation ability of HPCs derived from BM. J Acquir Immune Defic Syndr. 2016;71:467‐473.
    1. Castro P, Torres B, Lopez A, et al. Effects of different antigenic stimuli on thymic function and interleukin‐7/CD127 system in patients with chronic HIV infection. J Acquir Immune Defic Syndr. 2014;66:466‐472.
    1. Sandgaard KS, Lewis J, Adams S, et al. Antiretroviral therapy increases thymic output in children with HIV. AIDS. 2014;28:209‐214.
    1. de la Rosa R, Leal M, Rubio A, et al. Baseline thymic volume is a predictor for CD4 T cell repopulation in adult HIV‐infected patients under highly active antiretroviral therapy. Antivir Ther. 2002;7:159‐163.
    1. Ruiz‐Mateos E, Rubio A, Vallejo A, et al. Thymic volume is associated independently with the magnitude of short‐ and long‐term repopulation of CD4+ T cells in HIV‐infected adults after highly active antiretroviral therapy (HAART). Clin Exp Immunol. 2004;136:501‐506.
    1. Rosado‐Sanchez I, Herrero‐Fernandez I, Genebat M, et al. Thymic function impacts the peripheral CD4/CD8 ratio of HIV‐infected subjects. Clin Infect Dis. 2017;64:152‐158.
    1. McCune JM, Loftus R, Schmidt DK, et al. High prevalence of thymic tissue in adults with human immunodeficiency virus‐1 infection. J Clin Invest. 1998;101:2301‐2308.
    1. Kolte L, Dreves AM, Ersboll AK, et al. Association between larger thymic size and higher thymic output in human immunodeficiency virus‐infected patients receiving highly active antiretroviral therapy. J Infect Dis. 2002;185:1578‐1585.
    1. Shete A, Dhayarkar S, Sangale S, et al. Incomplete functional T‐cell reconstitution in immunological non‐responders at one year after initiation of antiretroviral therapy possibly predisposes them to infectious diseases. Int J Infect Dis. 2019;81:114‐122.
    1. Massanella M, Negredo E, Perez‐Alvarez N, et al. CD4 T‐cell hyperactivation and susceptibility to cell death determine poor CD4 T‐cell recovery during suppressive HAART. AIDS. 2010;24:959‐968.
    1. Rb‐Silva R, Nobrega C, Azevedo C, et al. Thymic function as a predictor of immune recovery in chronically HIV‐infected patients initiating antiretroviral therapy. Front Immunol. 2019;10:25.
    1. Li T, Wu N, Dai Y, et al. Reduced thymic output is a major mechanism of immune reconstitution failure in HIV‐infected patients after long‐term antiretroviral therapy. Clin Infect Dis. 2011;53(9):944‐951.
    1. Zakhour R, Tran DQ, Degaffe G, et al. Recent thymus emigrant CD4+ T cells predict HIV disease progression in patients with perinatally acquired HIV. Clin Infect Dis. 2016;62(8):1029‐1035.
    1. Ferrando‐Martinez S, De Pablo‐Bernal RS, De Luna‐Romero M, et al. Thymic function failure is associated with human immunodeficiency virus disease progression. Clin Infect Dis. 2017;64(9):1191‐1197.
    1. Cobos Jimenez V, Wit FW, Joerink M, et al. T‐Cell activation independently associates with immune senescence in HIV‐infected recipients of long‐term antiretroviral treatment. J Infect Dis. 2016;214(2):216‐225.
    1. Delobel P, Nugeyre MT, Cazabat M, et al. Naive T‐cell depletion related to infection by X4 human immunodeficiency virus type 1 in poor immunological responders to highly active antiretroviral therapy. J Virol. 2006;80(20):10229‐10236.
    1. Lu X, Su B, Xia H, et al. 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.
    1. Lundstrom W, Fewkes NM, Mackall CL. IL‐7 in human health and disease. Semin Immunol. 2012;24(3):218‐224.
    1. Raeber ME, Zurbuchen Y, Impellizzieri D, et al. The role of cytokines in T‐cell memory in health and disease. Immunol Rev. 2018;283(1):176‐193.
    1. Bai F, Bellistri GM, Tincati C, et al. Reduced CD127 expression on peripheral CD4+ T cells impairs immunological recovery in course of suppressive highly active antiretroviral therapy. AIDS. 2010;24(16):2590‐2593.
    1. Benito JM, Lopez M, Lozano S, et al. Down‐regulation of interleukin‐7 receptor (CD127) in HIV infection is associated with T cell activation and is a main factor influencing restoration of CD4(+) cells after antiretroviral therapy. J Infect Dis. 2008;198(10):1466‐1473.
    1. Hartling HJ, Jespersen S, Gaardbo JC, et al. Reduced IL‐7R T cell expression and increased plasma sCD127 in late presenting HIV‐infected individuals. J Acquir Immune Defic Syndr. 2017;74(1):81‐90.
    1. Shive CL, Clagett B, McCausland MR, et al. Inflammation perturbs the IL‐7 axis, promoting senescence and exhaustion that broadly characterize immune failure in treated HIV infection. J Acquir Immune Defic Syndr. 2016;71(5):483‐492.
    1. Clark RD, Fox PC. Statistical variation in progressive scrambling. J Comput Aided Mol Des. 2004;18(7‐9):563‐576.
    1. Rajasuriar R, Booth D, Solomon A, et al. Biological determinants of immune reconstitution in HIV‐infected patients receiving antiretroviral therapy: the role of interleukin 7 and interleukin 7 receptor alpha and microbial translocation. J Infect Dis. 2010;202(8):1254‐1264.
    1. Rethi B, Fluur C, Atlas A, et al. Loss of IL‐7Ralpha is associated with CD4 T‐cell depletion, high interleukin‐7 levels and CD28 down‐regulation in HIV infected patients. AIDS. 2005;19(18):2077‐2086.
    1. Napolitano LA, Grant RM, Deeks SG, et al. Increased production of IL‐7 accompanies HIV‐1‐mediated T‐cell depletion: implications for T‐cell homeostasis. Nat Med. 2001;7(1):73‐79.
    1. Nguyen TP, Shukla S, Asaad R, et al. Responsiveness to IL‐7 but not to IFN‐alpha is diminished in CD4+ T cells from treated HIV infected patients who experience poor CD4+ T‐cell recovery. AIDS. 2016;30(13):2033‐2042.
    1. Bellistri GM, Casabianca A, Merlini E, et al. Increased bone marrow interleukin‐7 (IL‐7)/IL‐7R levels but reduced IL‐7 responsiveness in HIV‐positive patients lacking CD4+ gain on antiviral therapy. PLoS One. 2010;5(12):e15663.
    1. Cote SC, Stilla A, Burke Schinkel SC, et al. IL‐7‐induced proliferation of peripheral Th17 cells is impaired in HAART‐controlled HIV infection. AIDS. 2019;33(6):985‐991.
    1. Lederman MM, Calabrese L, Funderburg NT, et al. Immunologic failure despite suppressive antiretroviral therapy is related to activation and turnover of memory CD4 cells. J Infect Dis. 2011;204(8):1217‐1226.
    1. Rosado‐Sanchez I, Jarrin I, Pozo‐Balado MM, et al. Higher levels of IL‐6, CD4 turnover and Treg frequency are already present before cART in HIV‐infected subjects with later low CD4 recovery. Antiviral Res. 2017;142:76‐82.
    1. Shive CL, Mudd JC, Funderburg NT, et al. Inflammatory cytokines drive CD4+ T‐cell cycling and impaired responsiveness to interleukin 7: implications for immune failure in HIV disease. J Infect Dis. 2014;210(4):619‐629.
    1. Kalayjian RC, Machekano RN, Rizk N, et al. Pretreatment levels of soluble cellular receptors and interleukin‐6 are associated with HIV disease progression in subjects treated with highly active antiretroviral therapy. J Infect Dis. 2010;201(12):1796‐1805.
    1. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5(10):e203.
    1. Zicari S, Sessa L, Cotugno N, et al. Immune activation, inflammation, and Non‐AIDS co‐morbidities in HIV‐infected patients under long‐term ART. Viruses. 2019;11(3).
    1. Yasuma‐Mitobe K, Matsuoka M. The roles of coinhibitory receptors in pathogenesis of human retroviral infections. Front Immunol. 2018;9:2755.
    1. Sperk M, Domselaar RV, Neogi U. Immune checkpoints as the immune system regulators and potential biomarkers in HIV‐1 infection. Int J Mol Sci. 2018;19(7).
    1. Banga R, Procopio FA, Noto A, et al. PD‐1(+) and follicular helper T cells are responsible for persistent HIV‐1 transcription in treated aviremic individuals. Nat Med. 2016;22(7):754‐761.
    1. Fromentin R, Bakeman W, Lawani MB, et al. CD4+ T cells expressing PD‐1, TIGIT and LAG‐3 contribute to HIV persistence during ART. PLoS Pathog. 2016;12(7):e1005761.
    1. Khoury G, Fromentin R, Solomon A, et al. Human immunodeficiency virus persistence and T‐cell activation in blood, rectal, and lymph node tissue in human immunodeficiency virus‐infected individuals receiving suppressive antiretroviral therapy. J Infect Dis. 2017;215(6):911‐919.
    1. Evans VA, van der Sluis RM, Solomon A, et al. Programmed cell death‐1 contributes to the establishment and maintenance of HIV‐1 latency. AIDS. 2018;32(11):1491‐1497.
    1. Day CL, Kaufmann DE, Kiepiela P, et al. PD‐1 expression on HIV‐specific T cells is associated with T‐cell exhaustion and disease progression. Nature. 2006;443(7109):350‐354.
    1. Hoffmann M, Pantazis N, Martin GE, et al. Exhaustion of activated CD8 T cells predicts disease progression in primary HIV‐1 infection. PLoS Pathog. 2016;12(7):e1005661.
    1. Nunnari G, Fagone P, Condorelli F, et al. CD4+ T‐cell gene expression of healthy donors, HIV‐1 and elite controllers: immunological chaos. Cytokine. 2016;83:127‐135.
    1. Yamamoto T, Price DA, Casazza JP, et al. Surface expression patterns of negative regulatory molecules identify determinants of virus‐specific CD8+ T‐cell exhaustion in HIV infection. Blood. 2011;117(18):4805‐4815.
    1. Tian X, Zhang A, Qiu C, et al. The upregulation of LAG‐3 on T cells defines a subpopulation with functional exhaustion and correlates with disease progression in HIV‐infected subjects. J Immunol. 2015;194(8):3873‐3882.
    1. Jones RB, Ndhlovu LC, Barbour JD, et al. Tim‐3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV‐1 infection. J Exp Med. 2008;205(12):2763‐2779.
    1. Cockerham LR, Jain V, Sinclair E, et al. Programmed death‐1 expression on CD4(+) and CD8(+) T cells in treated and untreated HIV disease. AIDS. 2014;28(12):1749‐1758.
    1. Noyan K, Nguyen S, Betts MR, et al. Human immunodeficiency virus type‐1 elite controllers maintain low co‐expression of inhibitory receptors on CD4+ T cells. Front Immunol. 2018;9:19.
    1. Grabmeier‐Pfistershammer K, Steinberger P, Rieger A, et al. Identification of PD‐1 as a unique marker for failing immune reconstitution in HIV‐1‐infected patients on treatment. J Acquir Immune Defic Syndr. 2011;56(2):118‐124.
    1. Hatano H, Jain V, Hunt PW, et al. Cell‐based measures of viral persistence are associated with immune activation and programmed cell death protein 1 (PD‐1)‐expressing CD4+ T cells. J Infect Dis. 2013;208(1):50‐56.
    1. Saidakova EV, Shmagel KV, Korolevskaya LB, et al. Lymphopenia‐induced proliferation of CD4 T‐cells is associated with CD4 T‐lymphocyte exhaustion in treated HIV‐infected patients. Indian J Med Res. 2018;147(4):376‐383.
    1. Appay V, Kelleher AD. Immune activation and immune aging in HIV infection. Curr Opin HIV AIDS. 2016;11(2):242‐249.
    1. Bruzzesi E, Sereti I. Residual immune activation and latency. Curr Top Microbiol Immunol. 2018;417:157‐180.
    1. Hileman CO, Funderburg NT. Inflammation, immune activation, and antiretroviral therapy in HIV. Curr HIV/AIDS Rep. 2017;14(3):93‐100.
    1. Sereti I, Krebs SJ, Phanuphak N, et al. Persistent, albeit reduced, chronic inflammation in persons starting antiretroviral therapy in acute HIV infection. Clin Infect Dis. 2017;64(2):124‐131.
    1. Tanko RF, Soares AP, Masson L, et al. Residual T cell activation and skewed CD8+ T cell memory differentiation despite antiretroviral therapy‐induced HIV suppression. Clin Immunol. 2018;195:127‐138.
    1. Gandhi RT, McMahon DK, Bosch RJ, et al. Levels of HIV‐1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation. PLoS Pathog. 2017;13(4):e1006285.
    1. Li JZ, Segal FP, Bosch RJ, et al. ART reduces T cell activation and immune exhaustion markers in HIV controllers. Clin Infect Dis. 2019.
    1. Kroeze S, Wit FW, Rossouw TM, et al. Plasma biomarkers of human immunodeficiency virus‐related systemic inflammation and immune activation in Sub‐Saharan Africa before and during suppressive antiretroviral therapy. J Infect Dis. 2019;220(6):1029‐1033.
    1. Hunt PW, Martin JN, Sinclair E, et al. 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.
    1. Vajpayee M, Kaushik S, Sreenivas V, et al. Role of immune activation in CD4+ T‐cell depletion in HIV‐1 infected Indian patients. Eur J Clin Microbiol Infect Dis. 2009;28(1):69‐73.
    1. Hunt PW, Cao HL, Muzoora C, et al. Impact of CD8+ T‐cell activation on CD4+ T‐cell recovery and mortality in HIV‐infected Ugandans initiating antiretroviral therapy. AIDS. 2011;25(17):2123‐2131.
    1. Zhang X, Hunt PW, Hammer SM, et al. Immune activation while on potent antiretroviral therapy can predict subsequent CD4+ T‐cell increases through 15 years of treatment. HIV Clin Trials. 2013;14(2):61‐67.
    1. Marchetti G, Gori A, Casabianca A, et al. 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.
    1. Negredo E, Massanella M, Puig J, et al. Nadir CD4 T cell count as predictor and high CD4 T cell intrinsic apoptosis as final mechanism of poor CD4 T cell recovery in virologically suppressed HIV‐infected patients: clinical implications. Clin Infect Dis. 2010;50(9):1300‐1308.
    1. Massanella M, Gomez‐Mora E, Carrillo J, et al. Increased ex vivo cell death of central memory CD4 T cells in treated HIV infected individuals with unsatisfactory immune recovery. J Transl Med. 2015;13:230.
    1. Ramirez CM, Sinclair E, Epling L, et al. Immunologic profiles distinguish aviremic HIV‐infected adults. AIDS. 2016;30(10):1553‐1562.
    1. Hansjee N, Kaufmann GR, Strub C, et al. Persistent apoptosis in HIV‐1‐infected individuals receiving potent antiretroviral therapy is associated with poor recovery of CD4 T lymphocytes. J Acquir Immune Defic Syndr. 2004;36(2):671‐677.
    1. Casetti R, Pinnetti C, Sacchi A, et al. HIV‐specific CD8 T cells producing CCL‐4 are associated with worse immune reconstitution during chronic infection. J Acquir Immune Defic Syndr. 2017;75(3):338‐344.
    1. Stiksrud B, Aass HCD, Lorvik KB, et al. Activated dendritic cells and monocytes in HIV immunological non‐responders; HIV‐induced IP‐10 correlates with low future CD4 recovery. AIDS. 2019.
    1. Stiksrud B, Lorvik KB, Kvale D, et al. Plasma IP‐10 is increased in immunological nonresponders and associated with activated regulatory T cells and persisting low CD4 counts. J Acquir Immune Defic Syndr. 2016;73(2):138‐148.
    1. Favre D, Mold J, Hunt PW, et al. Tryptophan catabolism by indoleamine 2,3‐dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med. 2010;2(32):32ra36.
    1. Byakwaga H, Boum Y, 2nd , Huang Y, et al. The kynurenine pathway of tryptophan catabolism, CD4+ T‐cell recovery, and mortality among HIV‐infected Ugandans initiating antiretroviral therapy. J Infect Dis. 2014;210(3):383‐391.
    1. Gaardbo JC, Trosied M, Stiksrud B, et al. Increased tryptophan catabolism is associated with increased frequency of CD161+Tc17/MAIT cells and lower CD4+ T‐cell count in HIV‐1 infected patients on cART after 2 years of follow‐up. J Acquir Immune Defic Syndr. 2015;70(3):228‐235.
    1. Luo Z, Li Z, Martin L, et al. Increased natural killer cell activation in HIV‐infected immunologic non‐responders correlates with CD4+ T cell recovery after antiretroviral therapy and viral suppression. PLoS One. 2017;12(1):e0167640.
    1. Bandera A, Masetti M, Fabbiani M, et al. The NLRP3 inflammasome is upregulated in HIV‐infected antiretroviral therapy‐treated individuals with defective immune recovery. Front Immunol. 2018;9:214.
    1. Bader J, Schoni‐Affolter F, Boni J, et al. Correlating HIV tropism with immunological response under combination antiretroviral therapy. HIV Med. 2016;17(8):615‐622.
    1. Dillon SM, Frank DN, Wilson CC. The gut microbiome and HIV‐1 pathogenesis: a two‐way street. AIDS. 2016;30(18):2737‐2751.
    1. Mudd JC, Brenchley JM. Gut mucosal barrier dysfunction, microbial dysbiosis, and their role in HIV‐1 disease progression. J Infect Dis. 2016;214(Suppl 2):S58‐66.
    1. Ramendra R, Isnard S, Mehraj V, et al. Circulating LPS and (1→3)‐beta‐D‐Glucan: a folie a deux contributing to HIV‐associated immune activation. Front Immunol. 2019;10:465.
    1. Gootenberg DB, Paer JM, Luevano JM, et al. HIV‐associated changes in the enteric microbial community: potential role in loss of homeostasis and development of systemic inflammation. Curr Opin Infect Dis. 2017;30(1):31‐43.
    1. Sandler NG, Douek DC. Microbial translocation in HIV infection: causes, consequences and treatment opportunities. Nat Rev Microbiol. 2012;10(9):655‐666.
    1. Jiang W, Lederman MM, Hunt P, et al. Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral‐treated HIV infection. J Infect Dis. 2009;199(8):1177‐1185.
    1. Mehraj V, Ramendra R, Isnard S, et al. Circulating (1→3)‐beta‐D‐Glucan is associated with immune activation during HIV infection. Clin Infect Dis. 2019.
    1. Nowak P, Troseid M, Avershina E, et al. Gut microbiota diversity predicts immune status in HIV‐1 infection. AIDS. 2015;29(18):2409‐2418.
    1. Lozupone CA, Li M, Campbell TB, et al. Alterations in the gut microbiota associated with HIV‐1 infection. Cell Host Microbe. 2013;14(3):329‐339.
    1. Dillon SM, Lee EJ, Kotter CV, et al. An altered intestinal mucosal microbiome in HIV‐1 infection is associated with mucosal and systemic immune activation and endotoxemia. Mucosal Immunol. 2014;7(4):983‐994.
    1. Mutlu EA, Keshavarzian A, Losurdo J, et al. A compositional look at the human gastrointestinal microbiome and immune activation parameters in HIV infected subjects. PLoS Pathog. 2014;10(2):e1003829.
    1. Vazquez‐Castellanos JF, Serrano‐Villar S, Latorre A, et al. Altered metabolism of gut microbiota contributes to chronic immune activation in HIV‐infected individuals. Mucosal Immunol. 2015;8(4):760‐772.
    1. Lu W, Feng Y, Jing F, et al. Association Between Gut Microbiota and CD4 Recovery in HIV‐1 Infected Patients. Front Microbiol. 2018;9:1451.
    1. Kaur US, Shet A, Rajnala N, et al. High abundance of genus Prevotella in the gut of perinatally HIV‐infected children is associated with IP‐10 levels despite therapy. Sci Rep. 2018;8(1):17679.
    1. Dillon SM, Lee EJ, Kotter CV, et al. Gut dendritic cell activation links an altered colonic microbiome to mucosal and systemic T‐cell activation in untreated HIV‐1 infection. Mucosal Immunol. 2016;9(1):24‐37.
    1. Lee SC, Chua LL, Yap SH, et al. Enrichment of gut‐derived Fusobacterium is associated with suboptimal immune recovery in HIV‐infected individuals. Sci Rep. 2018;8(1):14277.
    1. Perez‐Santiago J, Gianella S, Massanella M, et al. Gut Lactobacillales are associated with higher CD4 and less microbial translocation during HIV infection. AIDS. 2013;27(12):1921‐1931.
    1. Serpa JA, Rueda AM, Somasunderam A, et al. Long‐term use of proton pump inhibitors is associated with increased microbial product translocation, innate immune activation, and reduced immunologic recovery in patients with chronic human immunodeficiency virus‐1 infection. Clin Infect Dis. 2017;65(10):1638‐1643.
    1. Hawkins C, Christian B, Ye J, et al. Prevalence of hepatitis B co‐infection and response to antiretroviral therapy among HIV‐infected patients in Tanzania. AIDS. 2013;27(6):919‐927.
    1. Wandeler G, Gsponer T, Bihl F, et al. Hepatitis B virus infection is associated with impaired immunological recovery during antiretroviral therapy in the Swiss HIV cohort study. J Infect Dis. 2013;208(9):1454‐1458.
    1. van Griensven J, Phirum L, Choun K, et al. Hepatitis B and C co‐infection among HIV‐infected adults while on antiretroviral treatment: long‐term survival, CD4 cell count recovery and antiretroviral toxicity in Cambodia. PLoS One. 2014;9(2):e88552.
    1. Anderson M, Gaseitsiwe S, Moyo S, et al. Slow CD4(+) T‐cell recovery in human immunodeficiency virus/hepatitis B virus‐coinfected patients initiating truvada‐based combination antiretroviral therapy in Botswana. Open Forum Infect Dis. 2016;3(3):ofw140.
    1. Potter M, Odueyungbo A, Yang H, et al. Impact of hepatitis C viral replication on CD4+ T‐lymphocyte progression in HIV‐HCV coinfection before and after antiretroviral therapy. AIDS. 2010;24(12):1857‐1865.
    1. Marcus JL, Leyden WA, Chao CR, et al. Differences in response to antiretroviral therapy by sex and hepatitis C infection status. AIDS Patient Care STDS. 2015;29(7):370‐378.
    1. Chen M, Wong WW, Law MG, et al. Hepatitis B and C co‐infection in HIV patients from the TREAT Asia HIV observational database: analysis of risk factors and survival. PLoS One. 2016;11(3):e0150512.
    1. Appay V, Fastenackels S, Katlama C, et al. Old age and anti‐cytomegalovirus immunity are associated with altered T‐cell reconstitution in HIV‐1‐infected patients. AIDS. 2011;25(15):1813‐1822.
    1. Gomez‐Mora E, Massanella M, Garcia E, et al. Elevated humoral response to cytomegalovirus in HIV‐infected individuals with poor CD4+ T‐cell immune recovery. PLoS One. 2017;12(9):e0184433.
    1. Gonzalez VD, Falconer K, Blom KG, et al. High levels of chronic immune activation in the T‐cell compartments of patients coinfected with hepatitis C virus and human immunodeficiency virus type 1 and on highly active antiretroviral therapy are reverted by alpha interferon and ribavirin treatment. J Virol. 2009;83(21):11407‐11411.
    1. Idoko J, Meloni S, Muazu M, et al. Impact of hepatitis B virus infection on human immunodeficiency virus response to antiretroviral therapy in Nigeria. Clin Infect Dis. 2009;49(8):1268‐1273.
    1. Kovacs A, Al‐Harthi L, Christensen S, et al. CD8(+) T cell activation in women coinfected with human immunodeficiency virus type 1 and hepatitis C virus. J Infect Dis. 2008;197(10):1402‐1407.
    1. Patel EU, Gianella S, Newell K, et al. Elevated cytomegalovirus IgG antibody levels are associated with HIV‐1 disease progression and immune activation. AIDS. 2017;31(6):807‐813.
    1. Christensen‐Quick A, Massanella M, Frick A, et al. Subclinical cytomegalovirus DNA is associated with CD4 T cell activation and impaired CD8 T cell CD107a expression in people living with HIV despite early antiretroviral therapy. J Virol. 2019;93(13).
    1. Matthews GV, Manzini P, Hu Z, et al. Impact of lamivudine on HIV and hepatitis B virus‐related outcomes in HIV/hepatitis B virus individuals in a randomized clinical trial of antiretroviral therapy in southern Africa. AIDS. 2011;25(14):1727‐1735.
    1. Hamers RL, Zaaijer HL, Wallis CL, et al. HIV‐HBV coinfection in Southern Africa and the effect of lamivudine‐ versus tenofovir‐containing cART on HBV outcomes. J Acquir Immune Defic Syndr. 2013;64(2):174‐182.
    1. Anderson KB, Guest JL, Rimland D. Hepatitis C virus coinfection increases mortality in HIV‐infected patients in the highly active antiretroviral therapy era: data from the HIV Atlanta VA cohort study. Clin Infect Dis. 2004;39(10):1507‐1513.
    1. Peters L, Mocroft A, Soriano V, et al. Hepatitis C virus coinfection does not influence the CD4 cell recovery in HIV‐1‐infected patients with maximum virologic suppression. J Acquir Immune Defic Syndr. 2009;50(5):457‐463.
    1. Kapetanovic S, Aaron L, Montepiedra G, et al. Effect of cytomegalovirus co‐infection on normalization of selected T‐cell subsets in children with perinatally acquired HIV infection treated with combination antiretroviral therapy. PLoS One. 2015;10(3):e0120474.
    1. Estes JD. Pathobiology of HIV/SIV‐associated changes in secondary lymphoid tissues. Immunol Rev. 2013;254(1):65‐77.
    1. Schacker TW, Nguyen PL, Beilman GJ, et al. Collagen deposition in HIV‐1 infected lymphatic tissues and T cell homeostasis. J Clin Invest. 2002;110(8):1133‐1139.
    1. Diaz A, Alos L, Leon A, et al. Factors associated with collagen deposition in lymphoid tissue in long‐term treated HIV‐infected patients. AIDS. 2010;24(13):2029‐2039.
    1. Diaz A, Garcia F, Mozos A, et al. Lymphoid tissue collagen deposition in HIV‐infected patients correlates with the imbalance between matrix metalloproteinases and their inhibitors. J Infect Dis. 2011;203(6):810‐813.
    1. Schacker TW, Reilly C, Beilman GJ, et al. Amount of lymphatic tissue fibrosis in HIV infection predicts magnitude of HAART‐associated change in peripheral CD4 cell count. AIDS. 2005;19(18):2169‐2171.
    1. Zeng M, Southern PJ, Reilly CS, et al. Lymphoid tissue damage in HIV‐1 infection depletes naive T cells and limits T cell reconstitution after antiretroviral therapy. PLoS Pathog. 2012;8(1):e1002437.
    1. Seng R, Goujard C, Krastinova E, et al. Influence of lifelong cumulative HIV viremia on long‐term recovery of CD4+ cell count and CD4+/CD8+ ratio among patients on combination antiretroviral therapy. AIDS. 2015;29(5):595‐607.
    1. Ahn MY, Jiamsakul A, Khusuwan S, et al. The influence of age‐associated comorbidities on responses to combination antiretroviral therapy in older people living with HIV. J Int AIDS Soc. 2019;22(2):e25228.
    1. Greenblatt R, Bacchetti P, Boylan R, et al. Genetic and clinical predictors of CD4 lymphocyte recovery during suppressive antiretroviral therapy: whole exome sequencing and antiretroviral therapy response phenotypes. PLoS One. 2019;14(8):e0219201.
    1. Lee SS, Wong NS, Wong BCK, et al. Combining CD4 recovery and CD4: cD8 ratio restoration as an indicator for evaluating the outcome of continued antiretroviral therapy: an observational cohort study. BMJ Open. 2017;7(9):e016886.
    1. Tanuma J, Matsumoto S, Haneuse S, et al. Long‐term viral suppression and immune recovery during first‐line antiretroviral therapy: a study of an HIV‐infected adult cohort in Hanoi, Vietnam. J Int AIDS Soc. 2017;20(4).
    1. Boatman JA, Baker JV, Emery S, et al. Risk factors for low CD4+ count recovery despite viral suppression among participants initiating antiretroviral treatment with CD4+ counts >500 cells/mm3: findings from the Strategic Timing of AntiRetroviral Therapy (START) trial. J Acquir Immune Defic Syndr. 2019;81(1):10‐17.
    1. Roul H, Mary‐Krause M, Ghosn J, et al. CD4+ cell count recovery after combined antiretroviral therapy in the modern combined antiretroviral therapy era. AIDS. 2018;32(17):2605‐2614.
    1. Davy‐Mendez T, Napravnik S, Zakharova O, et al. Effectiveness of integrase strand transfer inhibitors among treatment‐experienced patients in a clinical setting. AIDS. 2019;33(7):1187‐1195.
    1. Gandhi RT, Spritzler J, Chan E, et al. Effect of baseline‐ and treatment‐related factors on immunologic recovery after initiation of antiretroviral therapy in HIV‐1‐positive subjects: results from ACTG 384. J Acquir Immune Defic Syndr. 2006;42(4):426‐434.
    1. Rosado‐Sanchez I, Herrero‐Fernandez I, Alvarez‐Rios AI, et al. A lower baseline CD4/CD8 T‐cell ratio is independently associated with immunodiscordant response to antiretroviral therapy in HIV‐infected subjects. Antimicrob Agents Chemother. 2017;61(8).
    1. Geng EH, Neilands TB, Thiebaut R, et al. CD41 T cell recovery during suppression of HIV replication: an international comparison of the immunological efficacy of antiretroviral therapy in North America, Asia and Africa. Int J Epidemiol. 2015;44(1):251‐263.
    1. Luz PM, Belaunzaran‐Zamudio PF, Crabtree‐Ramirez B, et al. CD4 response up to 5 years after combination antiretroviral therapy in human immunodeficiency virus‐infected patients in Latin America and the Caribbean. Open Forum Infect Dis. 2015;2(2):ofv079.
    1. de Monteynard LA, Matheron S, Gilquin J, et al. Influence of geographic origin, sex, and HIV transmission group on the outcome of first‐line combined antiretroviral therapy in France. AIDS. 2016;30(14):2235‐2246.
    1. Seng R, Ghislain M, Girard PM, et al. Sub‐Saharan African migrants have slower initial CD4+ cell recovery after combined antiretroviral treatment initiation than French natives. AIDS. 2017;31(9):1323‐1332.
    1. Luo Z, Li Z, Martin L, et al. Pathological role of anti‐CD4 antibodies in HIV‐infected immunologic nonresponders receiving virus‐suppressive antiretroviral therapy. J Infect Dis. 2017;216(1):82‐91.
    1. Lisco A, Wong CS, Lage SL, et al. Identification of rare HIV‐1‐infected patients with extreme CD4+ T cell decline despite ART‐mediated viral suppression. JCI Insight. 2019;4(8).
    1. Tincati C, Merlini E, Braidotti P, et al. Impaired gut junctional complexes feature late‐treated individuals with suboptimal CD4+ T‐cell recovery upon virologically suppressive combination antiretroviral therapy. AIDS. 2016;30(7):991‐1003.
    1. Agrati C, Tumino N, Bordoni V, et al. Myeloid derived suppressor cells expansion persists after early ART and may affect CD4 T cell recovery. Front Immunol. 2019;10:1886.
    1. Girard A, Vergnon‐Miszczycha D, Depince‐Berger AE, et al. Brief report: a high rate of beta7+ gut‐homing lymphocytes in HIV‐infected immunological nonresponders is associated with poor CD4 T‐cell recovery during suppressive HAART. J Acquir Immune Defic Syndr. 2016;72(3):259‐265.
    1. Rosado‐Sanchez I, Herrero‐Fernandez I, Genebat M, et al. HIV‐infected subjects with poor CD4 T‐cell recovery despite effective therapy express high levels of OX40 and alpha4beta7 on CD4 T‐cells prior therapy initiation. Front Immunol. 2018;9:1673.
    1. Sennepin A, Baychelier F, Guihot A, et al. NKp44L expression on CD4+ T cells is associated with impaired immunological recovery in HIV‐infected patients under highly active antiretroviral therapy. AIDS. 2013;27(12):1857‐1866.
    1. Ahuja SK, Kulkarni H, Catano G, et al. CCL3L1‐CCR5 genotype influences durability of immune recovery during antiretroviral therapy of HIV‐1‐infected individuals. Nat Med. 2008;14(4):413‐420.
    1. Yong YK, Shankar EM, Solomon A, et al. Polymorphisms in the CD14 and TLR4 genes independently predict CD4+ T‐cell recovery in HIV‐infected individuals on antiretroviral therapy. AIDS. 2016;30(14):2159‐2168.
    1. Guzman‐Fulgencio M, Berenguer J, Micheloud D, et al. European mitochondrial haplogroups are associated with CD4+ T cell recovery in HIV‐infected patients on combination antiretroviral therapy. J Antimicrob Chemother. 2013;68(10):2349‐2357.
    1. Medrano LM, Gutierrez‐Rivas M, Blanco J, et al. Mitochondrial haplogroup H is related to CD4+ T cell recovery in HIV infected patients starting combination antiretroviral therapy. J Transl Med. 2018;16(1):343.
    1. Andrade‐Santos JL, Carvalho‐Silva WHV, Coelho AVC, et al. IL18 gene polymorphism and its influence on CD4+ T‐cell recovery in HIV‐positive patients receiving antiretroviral therapy. Infect Genet Evol. 2019;75:103997.
    1. Resino S, Navarrete‐Munoz MA, Blanco J, et al. IL7RA rs6897932 polymorphism is associated with better CD4(+) T‐cell recovery in HIV infected patients starting combination antiretroviral therapy. Biomolecules. 2019;9(6).
    1. Hartling HJ, Thorner LW, Erikstrup C, et al. Polymorphism in interleukin‐7 receptor alpha gene is associated with faster CD4(+) T‐cell recovery after initiation of combination antiretroviral therapy. AIDS. 2014;28(12):1739‐1748.
    1. Hartling HJ, Ryder LP, Ullum H, et al. Gene variation in IL‐7 receptor (IL‐7R)alpha affects IL‐7R response in CD4+ T cells in HIV‐infected individuals. Sci Rep. 2017;7:42036.
    1. Restrepo C, Gutierrez‐Rivas M, Pacheco YM, et al. Genetic variation in CCR2 and CXCL12 genes impacts on CD4 restoration in patients initiating cART with advanced immunesupression. PLoS One. 2019;14(3):e0214421.
    1. El‐Beeli M, Al‐Mahrooqi SH, Youssef RM, et al. HLA‐A68 and HLA‐B15 alleles correlate with poor immune response among AIDS patients on combined antiretroviral therapy. Hum Immunol. 2016;77(6):490‐497.
    1. Joshi A, Punke EB, Mehmetoglu‐Gurbuz T, et al. TLR9 polymorphism correlates with immune activation, CD4 decline and plasma IP10 levels in HIV patients. BMC Infect Dis. 2019;19(1):56.
    1. Masson JJR, Cherry CL, Murphy NM, et al. Polymorphism rs1385129 within Glut1 gene SLC2A1 is linked to poor CD4+ T cell recovery in antiretroviral‐treated HIV+ individuals. Front Immunol. 2018;9:900.
    1. Garcia M, Jimenez‐Sousa MA, Blanco J, et al. CD4 recovery is associated with genetic variation in IFNgamma and IL19 genes. Antiviral Res. 2019;170:104577.
    1. Palermo B, Bosch RJ, Bennett K, et al. Body mass index and CD4+ T‐lymphocyte recovery in HIV‐infected men with viral suppression on antiretroviral therapy. HIV Clin Trials. 2011;12(4):222‐227.
    1. Koethe JR, Jenkins CA, Lau B, et al. Body mass index and early CD4 T‐cell recovery among adults initiating antiretroviral therapy in North America, 1998–2010. HIV Med. 2015;16(9):572‐577.
    1. Koethe JR, Jenkins CA, Lau B, et al. Higher time‐updated body mass index: association with improved CD4+ cell recovery on HIV treatment. J Acquir Immune Defic Syndr. 2016;73(2):197‐204.
    1. Li X, Ding H, Geng W, et al. Predictive effects of body mass index on immune reconstitution among HIV‐infected HAART users in China. BMC Infect Dis. 2019;19(1):373.
    1. Zaldivar F, McMurray RG, Nemet D, et al. Body fat and circulating leukocytes in children. Int J Obes (Lond). 2006;30(6):906‐911.
    1. Nowicki MJ, Karim R, Mack WJ, et al. Correlates of CD4+ and CD8+ lymphocyte counts in high‐risk immunodeficiency virus (HIV)‐seronegative women enrolled in the women's interagency HIV study (WIHS). Hum Immunol. 2007;68(5):342‐349.
    1. Womack J, Tien PC, Feldman J, et al. Obesity and immune cell counts in women. Metabolism. 2007;56(7):998‐1004.
    1. Palmer CS, Ostrowski M, Gouillou M, et al. Increased glucose metabolic activity is associated with CD4+ T‐cell activation and depletion during chronic HIV infection. AIDS. 2014;28(3):297‐309.
    1. Jimenez‐Sousa MA, Martinez I, Medrano LM, et al. Vitamin D in human immunodeficiency virus infection: influence on immunity and disease. Front Immunol. 2018;9:458.
    1. Ross AC, Judd S, Kumari M, et al. Vitamin D is linked to carotid intima‐media thickness and immune reconstitution in HIV‐positive individuals. Antivir Ther. 2011;16(4):555‐563.
    1. Aziz M, Livak B, Burke‐Miller J, et al. Vitamin D insufficiency may impair CD4 recovery among women's interagency HIV study participants with advanced disease on HAART. AIDS. 2013;27(4):573‐578.
    1. Ezeamama AE, Guwatudde D, Wang M, et al. Vitamin‐D deficiency impairs CD4+T‐cell count recovery rate in HIV‐positive adults on highly active antiretroviral therapy: a longitudinal study. Clin Nutr. 2016;35(5):1110‐1117.
    1. Shivakoti R, Ewald ER, Gupte N, et al. Effect of baseline micronutrient and inflammation status on CD4 recovery post‐cART initiation in the multinational PEARLS trial. Clin Nutr. 2018.
    1. Aguilar‐Jimenez W, Villegas‐Ospina S, Gonzalez S, et al. Precursor forms of vitamin d reduce HIV‐1 infection in vitro. J Acquir Immune Defic Syndr. 2016;73(5):497‐506.
    1. Rockstroh JK, Lennox JL, Dejesus E, et al. Long‐term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment‐naive human immunodeficiency virus‐1‐infected patients: 156‐week results from STARTMRK. Clin Infect Dis. 2011;53(8):807‐816.
    1. Edwards JK, Cole SR, Hall HI, et al. Virologic suppression and CD4+ cell count recovery after initiation of raltegravir or efavirenz‐containing HIV treatment regimens. AIDS. 2018;32(2):261‐266.
    1. Lennox JL, DeJesus E, Lazzarin A, et al. 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. Lancet. 2009;374(9692):796‐806.
    1. Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and safety of raltegravir versus efavirenz when combined with tenofovir/emtricitabine in treatment‐naive HIV‐1‐infected patients: final 5‐year results from STARTMRK. J Acquir Immune Defic Syndr. 2013;63(1):77‐85.
    1. Walmsley SL, Antela A, Clumeck N, et al. Dolutegravir plus abacavir‐lamivudine for the treatment of HIV‐1 infection. N Engl J Med. 2013;369(19):1807‐1818.
    1. Blanco JR, Alejos B, Moreno S. Impact of dolutegravir and efavirenz on immune recovery markers: results from a randomized clinical trial. Clin Microbiol Infect. 2018;24(8):900‐907.
    1. Zhang F, Sun M, Sun J, et al. The risk factors for suboptimal CD4 recovery in HIV infected population: an observational and retrospective study in Shanghai, China. Biosci Trends. 2015;9(5):335‐341.
    1. Bandera A, Colella E, Rizzardini G, et al. Strategies to limit immune‐activation in HIV patients. Expert Rev Anti Infect Ther. 2017;15(1):43‐54.
    1. Coelho L, Cardoso SW, Luz PM, et al. Vitamin D3 supplementation in HIV infection: effectiveness and associations with antiretroviral therapy. Nutr J. 2015;14:81.
    1. Fabre‐Mersseman V, Tubiana R, Papagno L, et al. Vitamin D supplementation is associated with reduced immune activation levels in HIV‐1‐infected patients on suppressive antiretroviral therapy. AIDS. 2014;28(18):2677‐2682.
    1. Eckard AR, O'Riordan MA, Rosebush JC, et al. Vitamin D supplementation decreases immune activation and exhaustion in HIV‐1‐infected youth. Antivir Ther. 2018;23(4):315‐324.
    1. Ashenafi S, Amogne W, Kassa E, et al. Daily nutritional supplementation with vitamin D(3) and phenylbutyrate to treatment‐naive HIV patients tested in a randomized placebo‐controlled trial. Nutrients. 2019;11(1).
    1. Onwumeh J, Okwundu CI, Kredo T. Interleukin‐2 as an adjunct to antiretroviral therapy for HIV‐positive adults. Cochrane Database Syst Rev. 2017;5:CD009818.
    1. Sereti I, Dunham RM, Spritzler J, et al. IL‐7 administration drives T cell‐cycle entry and expansion in HIV‐1 infection. Blood. 2009;113(25):6304‐6314.
    1. Levy Y, Lacabaratz C, Weiss L, et al. Enhanced T cell recovery in HIV‐1‐infected adults through IL‐7 treatment. J Clin Invest. 2009;119(4):997‐1007.
    1. Levy Y, Sereti I, Tambussi G, et al. Effects of recombinant human interleukin 7 on T‐cell recovery and thymic output in HIV‐infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo‐controlled, multicenter study. Clin Infect Dis. 2012;55(2):291‐300.
    1. Thiebaut R, Drylewicz J, Prague M, et al. Quantifying and predicting the effect of exogenous interleukin‐7 on CD4+ T cells in HIV‐1 infection. PLoS Comput Biol. 2014;10(5):e1003630.
    1. Sereti I, Estes JD, Thompson WL, et al. Decreases in colonic and systemic inflammation in chronic HIV infection after IL‐7 administration. PLoS Pathog. 2014;10(1):e1003890.
    1. Thiebaut R, Jarne A, Routy JP, et al. Repeated cycles of recombinant human interleukin 7 in HIV‐Infected patients with low CD4 T‐Cell Reconstitution on antiretroviral therapy: results of 2 phase II multicenter studies. Clin Infect Dis. 2016;62(9):1178‐1185.
    1. Katlama C, Lambert‐Niclot S, Assoumou L, et al. Treatment intensification followed by interleukin‐7 reactivates HIV without reducing total HIV DNA: a randomized trial. AIDS. 2016;30(2):221‐230.
    1. Zhang Z, Fu J, Xu X, et al. Safety and immunological responses to human mesenchymal stem cell therapy in difficult‐to‐treat HIV‐1‐infected patients. AIDS. 2013;27(8):1283‐1293.
    1. Saison J, Ferry T, Demaret J, et al. Association between discordant immunological response to highly active anti‐retroviral therapy, regulatory T cell percentage, immune cell activation and very low‐level viraemia in HIV‐infected patients. Clin Exp Immunol. 2014;176(3):401‐409.
    1. Jarrin I, Pantazis N, Dalmau J, et al. Does rapid HIV disease progression prior to combination antiretroviral therapy hinder optimal CD4+ T‐cell recovery once HIV‐1 suppression is achieved. AIDS. 2015;29(17):2323‐2333.
    1. Kim KH, Yi J, Lee SH. The CD4 slope can be a predictor of immunologic recovery in advanced HIV patients: a case‐control study. Korean J Intern Med. 2015;30(5):705‐713.
    1. Norris PJ, Zhang J, Worlock A, et al. Systemic cytokine levels do not predict CD4(+) T‐cell recovery after suppressive combination antiretroviral therapy in chronic human immunodeficiency virus infection. Open Forum Infect Dis. 2016;3(1):ofw025.
    1. Marziali M, De Santis W, Carello R, et al. 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.
    1. Engsig FN, Gerstoft J, Kronborg G, et al. Long‐term mortality in HIV patients virally suppressed for more than three years with incomplete CD4 recovery: a cohort study. BMC Infect Dis. 2010;10:318.
    1. Goicoechea M, Smith DM, Liu L, et al. Determinants of CD4+ T cell recovery during suppressive antiretroviral therapy: association of immune activation, T cell maturation markers, and cellular HIV‐1 DNA. J Infect Dis. 2006;194(1):29‐37.
    1. Tan R, Westfall AO, Willig JH, et al. Clinical outcome of HIV‐infected antiretroviral‐naive patients with discordant immunologic and virologic responses to highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2008;47(5):553‐558.
    1. Marchetti G, Gazzola L, Trabattoni D, et al. Skewed T‐cell maturation and function in HIV‐infected patients failing CD4+ recovery upon long‐term virologically suppressive HAART. AIDS. 2010;24(10):1455‐1460.
    1. Gaardbo JC, Hartling HJ, Ronit A, et al. Regulatory T cells in HIV‐infected immunological nonresponders are increased in blood but depleted in lymphoid tissue and predict immunological reconstitution. J Acquir Immune Defic Syndr. 2014;66(4):349‐357.
    1. Woelk CH, Beliakova‐Bethell N, Goicoechea M, et al. Gene expression before HAART initiation predicts HIV‐infected individuals at risk of poor CD4+ T‐cell recovery. AIDS. 2010;24(2):217‐222.
    1. Gomez‐Mora E, Garcia E, Urrea V, et al. Preserved immune functionality and high CMV‐specific T‐cell responses in HIV‐infected individuals with poor CD4(+) T‐cell immune recovery. Sci Rep. 2017;7(1):11711.
    1. Naftalin CM, Wong NS, Chan DP, et al. Three different patterns of CD4 recovery in a cohort of Chinese HIV patients following antiretroviral therapy ‐ a five‐year observational study. Int J STD AIDS. 2015;26(11):803‐809.
    1. Younes SA, Talla A, Pereira Ribeiro S, et al. Cycling CD4+ T cells in HIV‐infected immune nonresponders have mitochondrial dysfunction. J Clin Invest. 2018;128(11):5083‐5094.
    1. Gomez‐Mora E, Robert‐Hebmann V, Garcia E, et al. Brief report: impaired CD4 T‐cell response to autophagy in treated HIV‐1‐infected individuals. J Acquir Immune Defic Syndr. 2017;74(2):201‐205.
    1. Rosado‐Sanchez I, Rodriguez‐Gallego E, Peraire J, et al. Glutaminolysis and lipoproteins are key factors in late immune recovery in successfully treated HIV‐infected patients. Clin Sci (Lond). 2019;133(8):997‐1010.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera