Current HIV/AIDS Reports

, Volume 7, Issue 1, pp 4–10 | Cite as

Early Immune Senescence in HIV Disease



Non-AIDS-defining co-morbidities that occur despite viral suppression and immune reconstitution using antiretroviral therapy depict early aging process in HIV-infected individuals. During aging, a reduction in T-cell renewal, together with a progressive enrichment of terminally differentiated T cells, translates into a general decline of the immune system, gradually leading to immunosenescence. Inflammation is a hallmark of age-associated comorbidities, and immune activation is a hallmark of HIV disease. Constant stimulation of the immune system by HIV or due to co-infections activates the innate and adaptive immune system, resulting in release of mediators of inflammation. Immune activation coupled with lack of anti-inflammatory responses likely results in accelerated aging in HIV disease. Dysfunctional thymic output, along with HIV-mediated disruption of the gastrointestinal barrier leading to microbial translocation, contributes to the circulating antigenic load driving early senescence in HIV disease.


Senescene Activation Inflammation Microbial translocation 



Jules Levin, Executive Director and Founder, NATAP for driving our attention to important work done and to be done on aging and HIV research.


No potential conflicts of interest relevant to this article were reported.


  1. 1.
    Effros RB, Fletcher CV, Gebo K, et al.: Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions. Clin Infect Dis 2008, 47:542–553.CrossRefPubMedGoogle Scholar
  2. 2.
    Teichmann J, Stephan E, Discher T, et al.: Changes in calciotropic hormones and biochemical markers of bone metabolism in patients with human immunodeficiency virus infection. Metabolism 2000, 49:1134–1139.CrossRefPubMedGoogle Scholar
  3. 3.
    Kaplan RC, Kingsley LA, Sharrett AR, et al.: Ten-year predicted coronary heart disease risk in HIV-infected men and women. Clin Infect Dis 2007, 45:1074–1081CrossRefPubMedGoogle Scholar
  4. 4.
    Ikezu T: The aging of human-immunodeficiency-virus-associated neurocognitive disorders. J Neuroimmune Pharmacol 2009, 4:161–162.CrossRefPubMedGoogle Scholar
  5. 5.
    Desquilbet L, Margolick JB, Fried LP, et al.: Relationship between a frailty-related phenotype and progressive deterioration of the immune system in HIV-infected men. J Acquir Immune Defic Syndr 2009, 50:299–306.CrossRefPubMedGoogle Scholar
  6. 6.
    Pawelec G, Effros RB, Caruso C, et al.: T cells and aging (update february 1999). Front Biosci 1999, 4:D216–269.CrossRefPubMedGoogle Scholar
  7. 7.
    Hunt PW, Brenchley J, Sinclair E, et al.: Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis 2008, 197:126–133.CrossRefPubMedGoogle Scholar
  8. 8.
    Appay V, Sauce D: Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol 2008, 214:231–241.CrossRefPubMedGoogle Scholar
  9. 9.
    Deeks SG, Phillips AN: HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ 2009, 338:a3172.CrossRefPubMedGoogle Scholar
  10. 10.
    Piatak M Jr, Saag MS, Yang LC, et al.: High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 1993, 259:1749–1754.CrossRefPubMedGoogle Scholar
  11. 11.
    Hardy AW, Graham DR, Shearer GM, Herbeuval JP: HIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors by Toll-like receptor 7-induced IFN-alpha. Proc Natl Acad Sci U S A 2007, 104:17453–17458.CrossRefPubMedGoogle Scholar
  12. 12.
    Esser MT, Bess JW, Jr., Suryanarayana K, et al.: Partial activation and induction of apoptosis in CD4(+) and CD8(+) T lymphocytes by conformationally authentic noninfectious human immunodeficiency virus type 1. J Virol 2001;75:1152–1164.CrossRefPubMedGoogle Scholar
  13. 13.
    Kuller LH, Tracy R, Belloso W, et al.: Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008, 5:e203.CrossRefPubMedGoogle Scholar
  14. 14.
    Eggena MP, Barugahare B, Jones N, et al.: Depletion of regulatory T cells in HIV infection is associated with immune activation. J Immunol 2005, 174:4407–4414.PubMedGoogle Scholar
  15. 15.
    Giorgi JV, Lyles RH, Matud JL, et al.: Predictive value of immunologic and virologic markers after long or short duration of HIV-1 infection. J Acquir Immune Defic Syndr 2002, 29:346–355.PubMedGoogle Scholar
  16. 16.
    Czesnikiewicz-Guzik M, Lee WW, Cui D, et al.: T cell subset-specific susceptibility to aging. Clin Immunol 2008, 127:107–118.CrossRefPubMedGoogle Scholar
  17. 17.
    Cheng X, Yu X, Ding YJ, et al.: The Th17/Treg imbalance in patients with acute coronary syndrome. Clin Immunol 2008, 127:89–97.PubMedGoogle Scholar
  18. 18.
    Huang MC, Liao JJ, Bonasera S, et al.: Nuclear factor-kappaB-dependent reversal of aging-induced alterations in T cell cytokines. Faseb J 2008, 22:2142–2150.CrossRefPubMedGoogle Scholar
  19. 19.
    Caruso C, Candore G, Colonna-Romano G, et al.: Inflammation and life-span. Science 2005, 307:208–209; author reply 208–209.CrossRefPubMedGoogle Scholar
  20. 20.
    Ginaldi L, De Martinis M, Monti D, Franceschi C: Chronic antigenic load and apoptosis in immunosenescence. Trends Immunol 2005, 26:79–84.CrossRefPubMedGoogle Scholar
  21. 21.
    Linton PJ, Dorshkind K: Age-related changes in lymphocyte development and function. Nat Immunol 2004, 5:133–139.CrossRefPubMedGoogle Scholar
  22. 22.
    Kelley CF, Kitchen CM, Hunt PW, et al.: Incomplete peripheral CD4+ cell count restoration in HIV-infected patients receiving long-term antiretroviral treatment. Clin Infect Dis 2009, 48:787–794.CrossRefPubMedGoogle Scholar
  23. 23.
    Douek DC, McFarland RD, Keiser PH, et al.: Changes in thymic function with age and during the treatment of HIV infection. Nature 1998, 396:690–695.CrossRefPubMedGoogle Scholar
  24. 24.
    Lenschow DJ, Walunas TL, Bluestone JA: CD28/B7 system of T cell costimulation. Annu Rev Immunol 1996, 14:233–258.CrossRefPubMedGoogle Scholar
  25. 25.
    Spaulding C, Guo W, Effros RB: Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol 1999, 34:633–644.CrossRefPubMedGoogle Scholar
  26. 26.
    Merino J, Martinez-Gonzalez MA, Rubio M, et al.: Progressive decrease of CD8high+ CD28+ CD57− cells with ageing. Clin Exp Immunol 1998, 112:48–51.CrossRefPubMedGoogle Scholar
  27. 27.
    Brenchley JM, Karandikar NJ, Betts MR, et al.: Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood 2003, 101:2711–2720.CrossRefPubMedGoogle Scholar
  28. 28.
    Cao W, Jamieson BD, Hultin LE, et al.: Premature aging of T cells is associated with faster HIV-1 disease progression. J Acquir Immune Defic Syndr 2009, 50:137–147.CrossRefPubMedGoogle Scholar
  29. 29.
    Valenzuela HF, Effros RB: Divergent telomerase and CD28 expression patterns in human CD4 and CD8 T cells following repeated encounters with the same antigenic stimulus. Clin Immunol 2002, 105:117–125.CrossRefPubMedGoogle Scholar
  30. 30.
    Gamberg J, Pardoe I, Bowmer MI, et al.: Lack of CD28 expression on HIV-specific cytotoxic T lymphocytes is associated with disease progression. Immunol Cell Biol 2004, 82:38–46.CrossRefPubMedGoogle Scholar
  31. 31.
    Choremi-Papadopoulou H, Panagiotou N, Samouilidou E, et al.: CD28 costimulation and CD28 expression in T lymphocyte subsets in HIV-1 infection with and without progression to AIDS. Clin Exp Immunol 2000, 119:499–506.CrossRefPubMedGoogle Scholar
  32. 32.
    Choi BS, Park YK and Lee JS. The CD28/HLA-DR expressions on CD4+T but not CD8+T cells are significant predictors for progression to AIDS. Clin Exp Immunol 2002, 127:137–144.CrossRefPubMedGoogle Scholar
  33. 33.
    Desai SR, Usuga X, Martinson J, et al.: Immune senescence, activation and abnormal T cell homeostasis despite effective HAART, a hallmark of early aging in HIV. Presented at 16th Conference on Retroviruses and Opportunistic Infections. Montreal; February 8–11, 2009.Google Scholar
  34. 34.
    Bourgeois C, Hao Z, Rajewsky K, et al.: Ablation of thymic export causes accelerated decay of naïve CD4 T cells in the periphery because of activation by environmental antigen. Proc Natl Acad Sci U S A 2008, 105:8691–8696.CrossRefPubMedGoogle Scholar
  35. 35.
    Redelings MD, Sorvillo F, Mascola L: Increase in Clostridium difficile-related mortality rates, United States, 1999–2004. Emerg Infect Dis 2007, 13:1417–1419.PubMedGoogle Scholar
  36. 36.
    Cohen J: Retrovirus meeting. Back-to-basics push as HIV prevention struggles. Science 2008, 319:888.CrossRefPubMedGoogle Scholar
  37. 37.
    Brenchley JM, Price DA, Schacker TW, et al.: Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006, 12:1365–1371.CrossRefPubMedGoogle Scholar
  38. 38.
    Panda A, Arjona A, Sapey E, et al.: Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol 2009, 30:325–333.CrossRefPubMedGoogle Scholar
  39. 39.
    Renshaw M, Rockwell J, Engleman C, et al.: Cutting edge: impaired Toll-like receptor expression and function in aging. J Immunol 2002, 169:4697–4701.PubMedGoogle Scholar
  40. 40.
    Helenius M, Hanninen M, Lehtinen SK, Salminen A: Changes associated with aging and replicative senescence in the regulation of transcription factor nuclear factor-kappa B. Biochem J 1996, 318:603–608.PubMedGoogle Scholar
  41. 41.
    Hinojosa E, Boyd AR, Orihuela CJ: Age-associated inflammation and toll-like receptor dysfunction prime the lungs for pneumococcal pneumonia. J Infect Dis 2009, 200:546–554.CrossRefPubMedGoogle Scholar
  42. 42.
    van Duin D, Mohanty S, Thomas V, et al.: Age-associated defect in human TLR-1/2 function. J Immunol 2007, 178:970–975.PubMedGoogle Scholar
  43. 43.
    Stout-Delgado HW, Yang X, Walker WE, et al.: Aging impairs IFN regulatory factor 7 up-regulation in plasmacytoid dendritic cells during TLR9 activation. J Immunol 2008, 181:6747–6756.PubMedGoogle Scholar
  44. 44.
    Martinson J, Montoya CJ, Usuga X, et al.: Chloroquine modulates HIV-1 induced plasmacytoid dendritic cell IFNα: implication for T cell activation. Antimicrob Agent Chemother 2010, 54(2):871–881.CrossRefGoogle Scholar
  45. 45.
    Hatano H, Delwart EL, Norris PJ, et al.: Evidence for persistent low-level viremia in individuals who control human immunodeficiency virus in the absence of antiretroviral therapy. J Virol 2009, 83:329–335.CrossRefPubMedGoogle Scholar
  46. 46.
    Czeslick E, Struppert A, Simm A, Sablotzki A: E5564 (Eritoran) inhibits lipopolysaccharide-induced cytokine production in human blood monocytes. Inflamm Res 2006, 55:511–515.CrossRefPubMedGoogle Scholar
  47. 47.
    Connolly NC, Riddler SA, Rinaldo CR: Proinflammatory cytokines in HIV disease-a review and rationale for new therapeutic approaches. AIDS Rev 2005, 7:168–180.PubMedGoogle Scholar
  48. 48.
    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, 119:997–1007.PubMedGoogle Scholar
  49. 49.
    Dagarag M, Evazyan T, Rao N, Effros RB: Genetic manipulation of telomerase in HIV-specific CD8+ T cells: enhanced antiviral functions accompany the increased proliferative potential and telomere length stabilization. J Immunol 2004, 173:6303–6311.PubMedGoogle Scholar
  50. 50.
    Fauce SR, Jamieson BD, Chin AC, et al.: Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes. J Immunol 2008, 181:7400–7406.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Immunology/MicrobiologyRush University Medical CenterChicagoUSA

Personalised recommendations