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

English version České info

The CD4/CD8 ratio, a hallmark of the collection of T cell defects related to aging –“immunosenescence”- and a predictor of mortality in the general population, often fails to normalize in an important proportion of HIV-infected individuals with adequate CD4+ T cell recovery after ART initiation. However, the immunological and clinical characteristics of this clinical phenotype have not been elucidated. Herein we show that during treated HIV infection, expansion of CD8+ T cells, reflected as a low CD4/CD8 ratio, identifies a subgroup of individuals with a number of immunological abnormalities and a poor prognosis. These subjects exhibit increased innate and adaptive immune activation, an immunosenescent phenotype, CD4+ and CD8+ imbalance in the gut mucosa and higher risk of morbidity and mortality. In contrast, those who normalize the CD4/CD8 ratio have traits of a healthy immune system. We observed that early ART initiation might contribute to more rapid and robust CD4/CD8 ratio normalization compared to later initiation. Hence, the CD4/CD8 ratio might help to further discriminate the risk of disease progression of successfully treated HIV-infected individuals, and a successful response to ART may require both normalization of the peripheral CD4+ T cell count and the ratio of CD4+ to CD8+ T cell counts.

Vyšlo v časopise: 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 10(5): e32767. doi:10.1371/journal.ppat.1004078
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004078

Souhrn

Zdroje

1. LohseN, HansenAB, PedersenG, KronborgG, GerstoftJ, et al. (2007) Survival of persons with and without HIV infection in Denmark, 1995–2005. Ann Intern Med 146: 87–95.

2. BhaskaranK, HamoudaO, SannesM, BoufassaF, JohnsonAM, et al. (2008) Changes in the risk of death after HIV seroconversion compared with mortality in the general population. JAMA 300: 51–59 Available: http://www.ncbi.nlm.nih.gov/pubmed/18594040. Accessed 22 October 2013.

3. ZwahlenM, HarrisR, MayM, HoggR, CostagliolaD, et al. (2009) Mortality of HIV-infected patients starting potent antiretroviral therapy: comparison with the general population in nine industrialized countries. Int J Epidemiol 38: 1624–1633 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3119390&tool=pmcentrez&rendertype=abstract. Accessed 27 August 2013.

4. GuaraldiG, OrlandoG, ZonaS, MenozziM, CarliF, et al. (2011) Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis 53: 1120–1126 Available: http://www.ncbi.nlm.nih.gov/pubmed/21998278. Accessed 20 April 2013.

5. DeeksSG, TracyR, DouekDC (2013) Systemic Effects of Inflammation on Health during Chronic HIV Infection. Immunity 39: 633–645 Available: http://linkinghub.elsevier.com/retrieve/pii/S1074761313004354. Accessed 18 October 2013.

6. YoungJ, PsichogiouM, MeyerL, AyayiS, GrabarS, et al. (2012) 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 9: e1001194 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3308938&tool=pmcentrez&rendertype=abstract. Accessed 16 August 2013.

7. DeeksSG (2011) HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med 62: 141–155.

8. RodgerAJ, LodwickR, SchechterM, DeeksS, AminJ, et al. (2013) Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population. AIDS 27: 973–979 Available: http://www.ncbi.nlm.nih.gov/pubmed/23698063. Accessed 16 August 2013.

9. KullerLH, TracyR, BellosoW, De WitS, DrummondF, et al. (2008) Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 5: e203 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2570418&tool=pmcentrez&rendertype=abstract. Accessed 4 May 2011.

10. BoulwareDR, HullsiekKH, PuronenCE, RupertA, BakerJV, et al. (2011) Higher levels of CRP, D-dimer, IL-6, and hyaluronic acid before initiation of antiretroviral therapy (ART) are associated with increased risk of AIDS or death. J Infect Dis 203: 1637–1646 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3096784&tool=pmcentrez&rendertype=abstract. Accessed 18 October 2013.

11. JusticeAC, FreibergMS, TracyR, KullerL, TateJP, et al. (2012) Does an index composed of clinical data reflect effects of inflammation, coagulation, and monocyte activation on mortality among those aging with HIV? Clin Infect Dis 54: 984–994 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3297653&tool=pmcentrez&rendertype=abstract. Accessed 18 October 2013.

12. SubramanianS, TawakolA, BurdoTH, AbbaraS, WeiJ, et al. (2012) Arterial inflammation in patients with HIV. JAMA 308: 379–386 Available: http://www.ncbi.nlm.nih.gov/pubmed/23567304. Accessed 18 October 2013.

13. AppayV, FastenackelsS, KatlamaC, Ait-MohandH, SchneiderL, et al. (2011) Old age and anti-cytomegalovirus immunity are associated with altered T-cell reconstitution in HIV-1-infected patients. AIDS 25: 1813–1822 Available: http://www.ncbi.nlm.nih.gov/pubmed/21412126. Accessed 26 August 2013.

14. PapagnoL, SpinaCA, MarchantA, SalioM, RuferN, et al. (2004) Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection. PLoS Biol 2: E20 Available: http://dx.plos.org/10.1371/journal.pbio.0020020. Accessed 16 August 2013.

15. BorgesÁH, SilverbergMJ, WentworthD, GrulichAE, FätkenheuerG, et al. (2013) Predicting risk of cancer during HIV infection: the role of inflammatory and coagulation biomarkers. AIDS 27: 1433–1441 Available: http://www.ncbi.nlm.nih.gov/pubmed/23945504. Accessed 27 August 2013.

16. DuprezDA, NeuhausJ, KullerLH, TracyR, BellosoW, et al. (2012) Inflammation, coagulation and cardiovascular disease in HIV-infected individuals. PLoS One 7: e44454 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3438173&tool=pmcentrez&rendertype=abstract. Accessed 27 August 2013.

17. NeuhausJ, AngusB, KowalskaJD, La RosaA, SampsonJ, et al. (2010) Risk of all-cause mortality associated with nonfatal AIDS and serious non-AIDS events among adults infected with HIV. AIDS 24: 697–706 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2897168&tool=pmcentrez&rendertype=abstract. Accessed 22 October 2013.

18. MarchettiG, Cozzi-LepriA, MerliniE, BellistrìGM, CastagnaA, et al. (2011) Microbial translocation predicts disease progression of HIV-infected antiretroviral-naive patients with high CD4+ cell count. AIDS 25: 1385–1394 Available: http://www.ncbi.nlm.nih.gov/pubmed/21505312. Accessed 18 October 2013.

19. HuntPW, CaoHL, MuzooraC, SsewanyanaI, BennettJ, et al. (2011) Impact of CD8+ T-cell activation on CD4+ T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy. AIDS 25: 2123–2131 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3480326&tool=pmcentrez&rendertype=abstract. Accessed 21 October 2013.

20. FunderburgNT, MayneE, SiegSF, AsaadR, JiangW, et al. (2010) Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation. Blood 115: 161–167 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2808148&tool=pmcentrez&rendertype=abstract. Accessed 18 October 2013.

21. Méndez-LagaresG, Romero-SánchezMC, Ruiz-MateosE, GenebatM, Ferrando-MartínezS, et al. (2013) Long-term suppressive combined antiretroviral treatment does not normalize the serum level of soluble CD14. J Infect Dis 207: 1221–1225 Available: http://jid.oxfordjournals.org/content/207/8/1221.short. Accessed 18 October 2013.

22. FavreD, MoldJ, HuntPW, KanwarB, LokeP, et al. (2010) Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med 2: 32ra36 Available: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3034445/. Accessed 2 December 2013.

23. MargolickJB, MuñozA, DonnenbergAD, ParkLP, GalaiN, et al. (1995) Failure of T-cell homeostasis preceding AIDS in HIV-1 infection. The Multicenter AIDS Cohort Study. Nat Med 1: 674–680 Available: http://www.ncbi.nlm.nih.gov/pubmed/7585150. Accessed 21 October 2013.

24. Devitt E, Rodríguez JM, Pozniak A (2013) CD4 but not CD4:CD8 ratio recovery after 14 years successful HIV suppression [Abstract 311]. In: Proceedings of the 20th Conference on Retrovirus and Opportunistic Infections; 3–6 March 2013; Atlanta, Georgia, United States. CROI 2013.

25. HadrupSR, StrindhallJ, KøllgaardT, JohanssonB, PawelecG, et al. (2006) Longitudinal Studies of Clonally Expanded CD8 T Cells Reveal a Repertoire Shrinkage Predicting Mortality and an Increased Number of Dysfunctional Cytomegalovirus-Specific T Cells in the Very Elderly. J Immunol 176: 2645–2653 Available: http://www.jimmunol.org/content/176/4/2645.short. Accessed 28 August 2013.

26. FergusonFG, WikbyA, MaxsonP, OlssonJ, JohanssonB (1995) Immune parameters in a longitudinal study of a very old population of Swedish people: a comparison between survivors and nonsurvivors. J Gerontol A Biol Sci Med Sci 50: B378–B382.

27. WikbyA, FergusonF, ForseyR, ThompsonJ, StrindhallJ, et al. (2005) An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans. J Gerontol A Biol Sci Med Sci 60: 556–565.

28. StrindhallJ, SkogM, ErnerudhJ, BengnerM, LöfgrenS, et al. (2013) The inverted CD4/CD8 ratio and associated parameters in 66-year-old individuals: the Swedish HEXA immune study. Age (Dordr) 35: 985–991 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3636392&tool=pmcentrez&rendertype=abstract. Accessed 18 October 2013.

29. WikbyA, NilssonB-O, ForseyR, ThompsonJ, StrindhallJ, et al. (2006) The immune risk phenotype is associated with IL-6 in the terminal decline stage: findings from the Swedish NONA immune longitudinal study of very late life functioning. Mech Ageing Dev 127: 695–704 Available: http://www.ncbi.nlm.nih.gov/pubmed/16750842. Accessed 16 May 2013.

30. MargolickJBJ, GangeSSJ, DetelsR, O'GormanMRG, RinaldoCR, et al. (2006) Impact of inversion of the CD4/CD8 ratio on the natural history of HIV-1 infection. J Acquir Immune Defic Syndr 42: 620–626 Available: http://journals.lww.com/jaids/Abstract/2006/08150/Impact_of_Inversion_of_the_CD4_CD8_Ratio_on_the.16.aspx. Accessed 9 August 2013.

31. TortiC, ProsperiM, MottaD, DigiambenedettoS, MaggioloF, et al. (2012) Factors influencing the normalization of CD4+ T-cell count, percentage and CD4+/CD8+ T-cell ratio in HIV-infected patients on long-term suppressive antiretroviral therapy. Clin Microbiol Infect 18: 449–458 Available http://www.ncbi.nlm.nih.gov/pubmed/21919996.

32. Serrano-VillarS, GutiérrezC, VallejoA, Hernández-NovoaB, DíazL, et al. (2013) The CD4/CD8 ratio in HIV-infected subjects is independently associated with T-cell activation despite long-term viral suppression. J Infect 66: 57–66 Available: http://www.ncbi.nlm.nih.gov/pubmed/23046968. Accessed 17 July 2013.

33. SainzT, Serrano-VillarS, DíazL, González-ToméMI, GurbindoMD, et al. (2013) The CD4/CD8 Ratio as a Marker T-cell Activation, Senescence and Activation/Exhaustion in Treated HIV-Infected Children and Young Adults. AIDS 27: 1513–1516 Available: http://www.ncbi.nlm.nih.gov/pubmed/23435292. Accessed 28 February 2013.

34. Serrano-VillarS, MorenoS, Fuentes-FerrerM, Sánchez-MarcosC, AvilaM, et al. (2014) The CD4:CD8 ratio is associated with markers of age-associated disease in virally suppressed HIV-infected patients with immunological recovery. HIV Med 15: 40–49 Available: http://www.ncbi.nlm.nih.gov/pubmed/24007533. Accessed 10 December 2013.

35. LoJ, AbbaraS, ShturmanL, SoniA, WeiJ, et al. (2010) Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men. AIDS 24: 243–253 Available: http://www.ncbi.nlm.nih.gov/pubmed/19996940. Accessed 30 May 2011.

36. Serrano-VillarS, Pérez-ElíasMJ, DrondaF, CasadoJL, MorenoA, et al. (2014) Increased Risk of Serious Non-AIDS-Related Events in HIV-Infected Subjects on Antiretroviral Therapy Associated with a Low CD4/CD8 Ratio. PLoS ONE 9(1): e85798 doi:10.1371/journal.pone.0085798. Accessed 1 March 2014

37. JainV, HartogensisW, BacchettiP, HuntPW, HatanoH, et al. (2013) Antiretroviral Therapy Initiated Within 6 Months of HIV Infection Is Associated With Lower T-Cell Activation and Smaller HIV Reservoir Size. J Infect Dis 208: 1202–1211 Available: http://www.ncbi.nlm.nih.gov/pubmed/23852127. Accessed 18 October 2013.

38. HatanoH, HayesTL, DahlV, SinclairE, LeeT-H, et al. (2011) A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a suboptimal CD4+ T cell response. J Infect Dis 203: 960–968 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3068029&tool=pmcentrez&rendertype=abstract. Accessed 12 August 2013.

39. HuntPW, ShulmanNS, HayesTL, DahlV, SomsoukM, et al. (2013) The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial. Blood 121: 4635–4646 Available: http://www.ncbi.nlm.nih.gov/pubmed/23589670. Accessed 15 August 2013.

40. Hsue P, Scherzer R, Gilman L, Wu Y, Maka K, et al.. (2012) Maraviroc Intensification on Endothelial Function in Treated HIV Infection [Abstract 123]. In: Proceedings of the 19th Conference on Retroviruses and Opportunistic Infections; 5–8 March 2012; Seattle, Washington, United States. CROI 2012.

41. HatanoH, JainV, HuntPW, LeeT-H, SinclairE, et al. (2013) 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 208: 50–56 Available: http://www.ncbi.nlm.nih.gov/pubmed/23089590. Accessed 21 August 2013.

42. ShacklettBL, YangO, HausnerMA, ElliottJ, HultinL, et al. (2003) Optimization of methods to assess human mucosal T-cell responses to HIV infection. J Immunol Methods 279: 17–31 Available: http://linkinghub.elsevier.com/retrieve/pii/S0022175903002552. Accessed 11 May 2013.

43. LeeSA, SinclairE, HatanoH, HsuePY, EplingL, et al. (2014) Impact of HIV on CD8+ T Cell CD57 Expression Is Distinct from That of CMV and Aging. PLoS ONE 9(2): e89444 doi:10.1371/journal.pone.0089444. Accessed 1 March 2014

44. NaegerDM, MartinJN, SinclairE, HuntP, BangsbergDR, et al. (2010) Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV disease. PLoS One 5: e8886 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2813282&tool=pmcentrez&rendertype=abstract. Accessed 6 May 2013.

45. WikbyA, MaxsonP, OlssonJ, JohanssonB, FergusonFG (1998) Changes in CD8 and CD4 lymphocyte subsets, T cell proliferation responses and non-survival in the very old: the Swedish longitudinal OCTO-immune study. Mech Ageing Dev 102: 187–198.

46. DeeksSG, VerdinE, McCuneJM (2012) Immunosenescence and HIV. Curr Opin Immunol 24: 501–506 Available: http://www.ncbi.nlm.nih.gov/pubmed/22658763. Accessed 24 September 2013.

47. DesaiS, LandayA (2010) Early immune senescence in HIV disease. Curr HIV/AIDS Rep 7: 4–10 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3739442&tool=pmcentrez&rendertype=abstract. Accessed 18 October 2013.

48. DockJN, EffrosRB (2011) Role of CD8 T Cell Replicative Senescence in Human Aging and in HIV-mediated Immunosenescence. Aging Dis 2: 382–397 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3269814&tool=pmcentrez&rendertype=abstract. Accessed 18 October 2013.

49. BrenchleyJM, KarandikarNJ, BettsMR, AmbrozakDR, HillBJ, et al. (2003) Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood 101: 2711–2720 Available: http://www.ncbi.nlm.nih.gov/pubmed/12433688. Accessed 2 March 2013.

50. MonteiroJ, BatliwallaF, OstrerH, GregersenPK (1996) Shortened telomeres in clonally expanded CD28−CD8+ T cells imply a replicative history that is distinct from their CD28+CD8+ counterparts. J Immunol 156: 3587–3590 Available: http://www.jimmunol.org/content/156/10/3587.abstract. Accessed 9 August 2013.

51. EffrosRB, AllsoppR, ChiuCP, HausnerMA, HirjiK, et al. (1996) Shortened telomeres in the expanded CD28−CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis. AIDS 10: F17–22 Available: http://www.ncbi.nlm.nih.gov/pubmed/8828735. Accessed 5 September 2013.

52. Vujkovic-CvijinI, DunhamRM, IwaiS, MaherMC, AlbrightRG, et al. (2013) Dysbiosis of the Gut Microbiota Is Associated with HIV Disease Progression and Tryptophan Catabolism. Sci Transl Med 5: 193ra91 Available: http://stm.sciencemag.org/cgi/doi/10.1126/scitranslmed.3006438. Accessed 10 July 2013.

53. ChevalierMF, PetitjeanG, Dunyach-RémyC, DidierC, GirardP-M, et al. (2013) The Th17/Treg ratio, IL-1RA and sCD14 levels in primary HIV infection predict the T-cell activation set point in the absence of systemic microbial translocation. PLoS Pathog 9: e1003453 Available: http://dx.plos.org/10.1371/journal.ppat.1003453. Accessed 18 October 2013.

54. Van SighemAI, GrasLAJ, ReissP, BrinkmanK, de WolfF (2010) Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of uninfected individuals. AIDS 24: 1527–1535 Available: http://www.ncbi.nlm.nih.gov/pubmed/20467289. Accessed 27 August 2013.

55. LewdenC, CheneG, MorlatP, RaffiF, DuponM, et al. (2007) 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 46: 72–77.

56. LewdenC, BouteloupV, DeWS, SabinC, MocroftA, et al. (2012) All-cause mortality in treated HIV-infected adults with CD4 ≥500/mm3 compared with the general population: evidence from a large European observational cohort collaboration. Int J Epidemiol 41: 433–445 Available: http://www.ncbi.nlm.nih.gov/pubmed/22493325. Accessed 27 August 2013.

57. AnglaretX, MingaA, GabillardD, OuassaT, MessouE, et al. (2012) AIDS and non-AIDS morbidity and mortality across the spectrum of CD4 cell counts in HIV-infected adults before starting antiretroviral therapy in Cote d'Ivoire. Clin Infect Dis 54: 714–723 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3275759&tool=pmcentrez&rendertype=abstract. Accessed 23 August 2013.

58. LadellK, HellersteinMK, CesarD, BuschR, BobanD, et al. (2008) Central memory CD8+ T cells appear to have a shorter lifespan and reduced abundance as a function of HIV disease progression. J Immunol 180: 7907–7918 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2562545&tool=pmcentrez&rendertype=abstract. Accessed 26 September 2013.

59. ZengM, SouthernPJ, ReillyCS, BeilmanGJ, ChipmanJG, et al. (2012) Lymphoid tissue damage in HIV-1 infection depletes naïve T cells and limits T cell reconstitution after antiretroviral therapy. PLoS Pathog 8: e1002437 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3252371&tool=pmcentrez&rendertype=abstract. Accessed 26 September 2013.

60. EstesJ, BakerJV, BrenchleyJM, KhorutsA, BartholdJL, et al. (2008) Collagen deposition limits immune reconstitution in the gut. J Infect Dis 198: 456–464 Available: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2683984&tool=pmcentrez&rendertype=abstract. Accessed 26 September 2013.

61. ChunT-WW, JustementJS, PandyaP, HallahanCW, McLaughlinM, et al. (2002) Relationship between the size of the human immunodeficiency virus type 1 (HIV-1) reservoir in peripheral blood CD4+ T cells and CD4+:CD8+ T cell ratios in aviremic HIV-1-infected individuals receiving long-term highly active antiretroviral therapy. J Infect Dis 185: 1672–1676 Available http://www.ncbi.nlm.nih.gov/pubmed/12023777.

62. Fourati S, Calin R, Carcelain G, Flandre P, Soulie C, et al. (2013) Factors associated with a low HIV reservoir in patients with prolonged suppressive antiretroviral therapy. Abstract WEPE443. In: Proceedings of the 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention. 30 June–3 July 2013; Kuala Lumpur, Malaysia. IAS 2013. Available: http://pag.ias2013.org/Abstracts.aspx?AID=1436. Accessed 2 February 2014.