Skip to main content

Advertisement

SpringerLink
Log in

Understanding Frailty, Aging, and Inflammation in HIV Infection

  • HIV Pathogenesis and Treatment (AL Landay, Section Editor)
  • Published:
Current HIV/AIDS Reports Aims and scope Submit manuscript

Abstract

Frailty is a clinical syndrome initially characterized in geriatric populations with a hallmark of age-related declines in physiologic reserve and function and increased vulnerability to adverse health outcomes. Recently, frailty has increasingly been recognized as a common and important HIV-associated non-AIDS (HANA) condition. This article provides an overview of our current understanding of frailty and its phenotypic characteristics and evidence that they are related to aging and to chronic inflammation that is associated with aging and also with long-term treated HIV infection. The etiology of this chronic inflammation is unknown but we discuss evidence linking it to persistent infection with cytomegalovirus in both geriatric populations and people living with HIV infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Desquilbet L, Jacobson L, Fried LP, Phair JP, Williams CM, Jamieson BD, et al. HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty. J Gerontol A Biol Sci Med Sci. 2007;62:1279–86.

    Article  PubMed  Google Scholar 

  2. Piggott DA, Muzaale AD, Mehta SH, Brown TT, Patel KV, Leng SX, et al. Frailty, HIV infection, and mortality in an aging cohort of injection drug users. PLoS ONE. 2013;8(1):e54910. This study demonstrated the prognostic import of frailty in a cohort of injection drug users with HIV infcction.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Desquilbet L, Margolick JB, Fried LP, Phair JP, Jamieson BD, Holloway M, et al. Relationship between a frailty-related phenotype and progressive deterioration of the immune system in HIV-1 infected men. J Acquir Immun Defic Syndr. 2009;50:299–306. This study illustrated the relationship between the frailty-related phenotype studied and the CD4 cell count in HIV-infected and -uninfected men who have sex with men.

    Article  Google Scholar 

  4. Terzian AS, Holman S, Nathwani N, Robison E, Weber K, Young M, et al. Factors associated with preclinical disability and frailty among HIV-infected and HIV-uninfected women in the era of cART. J Womens Health (Larchmt). 2009;18(12):1965–74.

    Article  Google Scholar 

  5. Pathai S, Gilbert C, Weiss HA, Cook C, Wood R, Bekker LG, et al. Frailty in HIV-infected adults in South Africa. J Acquir Immune Defic Syndr. 2013;62(1):43–51.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Akgün KM, Tate JP, Crothers K, Crystal S, Leaf DA, Womack J, et al. An adapted frailty-related phenotype and the VACS index as predictors of hospitalization and mortality in HIV-infected and uninfected individuals. JAIDS. 2014;67:397–404. Using a modified frailty phenotype, this study demonstrated the clinical import of frailty in HIV-infected and -unifected veterans.

    PubMed  Google Scholar 

  7. Fried L, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol Med Sci. 2001;56A:M146–56. This paper described the frailty phenotype that has been most widely used and is focused on in the present review.

    Article  Google Scholar 

  8. Bandeen-Roche K, Xue QL, Ferrucci L, Walston J, Guralnik JM, Chaves P, et al. Phenotype of frailty: characterization in the women’s health and aging studies. J Gerontol A Biol Sci Med Sci. 2006;61(3):262–6.

    Article  PubMed  Google Scholar 

  9. Lipsitz LA. Dynamics of stability: the physiologic basis of functional health and frailty. J Gerontol A Biol Sci Med Sci. 2002;57(3):B115–25.

    Article  PubMed  Google Scholar 

  10. Fried LP, Hadley EC, Walston JD, Newman AB, Guralnik JM, Studenski S, et al. From bedside to bench: research agenda for frailty. Sci Aging Knowl Environ. 2005;2005(31):e24.

    Article  Google Scholar 

  11. Walston J, Hadley EC, Ferrucci L, Guralnik JM, Newman AB, Studenski SA, et al. Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc. 2006;54(6):991–1001.

    Article  PubMed  Google Scholar 

  12. Yao X, Li H, Leng SX. Inflammation and immune system alterations in frailty. Clin Geriatr Med. 2011;27(1):79–87.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Chen X, Mao G, Leng SX. Frailty syndrome: an overview. Clin Interv Aging. 2014;9:433–41.

    PubMed Central  PubMed  Google Scholar 

  14. Morley JE, Vellas B, van Kan GA, Anker SD, Bauer JM, Bernabei R, et al. Frailty consensus: a call to action. J Am Med Dir Assoc. 2013;14(6):392–7. This paper reviews the basis for considering frailty as a clnical syndrome that merits attention in clinical care.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Fried LP, Xue QL, Cappola AR, Ferrucci L, Chaves P, Varadhan R, et al. Nonlinear multisystem physiological dysregulation associated with frailty in older women: implications for etiology and treatment. J Gerontol A Biol Sci Med Sci. 2009;64(10):1049–57. This paper explores the multisystem nature of frailty.

    Article  PubMed  Google Scholar 

  16. Jones DM, Song X, Rockwood K. Operationalizing a frailty index from a standardized comprehensive geriatric assessment. J Am Geriatr Soc. 2004;52(11):1929–33.

    Article  PubMed  Google Scholar 

  17. Brothers TD, Kirkland S, Guaraldi G, Falutz J, Theou O, Johnston BL, et al. Frailty in people aging with human immunodeficiency virus (HIV) infection. J Infect Dis. 2014;210(8):1170–9. This paper reviews the clinical aspects of frailty and studies of frailty in people living with HIV infection.

    Article  PubMed  Google Scholar 

  18. Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J Gerontol A Biol Sci Med Sci. 2004;59(3):255–63.

    Article  PubMed  Google Scholar 

  19. Santos-Eggimann B, Cuenoud P, Spagnoli J, Junod J. Prevalence of frailty in middle-aged and older community-dwelling Europeans living in 10 countries. J Gerontol A Biol Sci Med Sci. 2009;64(6):675–81.

    Article  PubMed  Google Scholar 

  20. Alvarado BE, Zunzunegui MV, Beland F, Bamvita JM. Life course social and health conditions linked to frailty in Latin American older men and women. J Gerontol A Biol Sci Med Sci. 2008;63(12):1399–406.

    Article  PubMed  Google Scholar 

  21. Buchman AS, Boyle PA, Wilson RS, Tang Y, Bennett DA. Frailty is associated with incident Alzheimer’s disease and cognitive decline in the elderly. Psychosom Med. 2007;69(5):483–9.

    Article  PubMed  Google Scholar 

  22. Makary MA, Segev DL, Pronovost PJ, Syin D, Bandeen-Roche K, Patel P, et al. Frailty as a predictor of surgical outcomes in older patients. J Am Coll Surg. 2010;210(6):901–8.

    Article  PubMed  Google Scholar 

  23. Ronning B, Wyller TB, Seljeflot I, Jordhoy MS, Skovlund E, Nesbakken A, et al. Frailty measures, inflammatory biomarkers and post-operative complications in older surgical patients. Age Ageing. 2010;39(6):758–61.

    Article  PubMed  Google Scholar 

  24. Audisio RA, van Leeuwen B. When reporting on older patients with cancer, frailty information is needed. Ann Surg Oncol. 2011;18(1):4–5.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Courtney-Brooks M, Tellawi AR, Scalici J, Duska LR, Jazaeri AA, Modesitt SC, et al. Frailty: an outcome predictor for elderly gynecologic oncology patients. Gynecol Oncol. 2012;126(1):20–4.

    Article  PubMed  Google Scholar 

  26. Aaldriks AA, van der Geest LG, Giltay EJ, le Cessie S, Portielje JE, Tanis BC, et al. Frailty and malnutrition predictive of mortality risk in older patients with advanced colorectal cancer receiving chemotherapy. J Geriatr Oncol. 2013;4(3):218–26.

    Article  PubMed  Google Scholar 

  27. Iqbal J, Denvir M, Gunn J. Frailty assessment in elderly people. Lancet. 2013;381(9882):1985–6.

    Article  PubMed  Google Scholar 

  28. McAdams-DeMarco MA, Suresh S, Law A, Salter ML, Gimenez LF, Jaar BG, et al. Frailty and falls among adult patients undergoing chronic hemodialysis: a prospective cohort study. BMC Nephrol. 2013;14:224.

    Article  PubMed Central  PubMed  Google Scholar 

  29. McAdams-DeMarco MA, Law A, Tan J, Delp C, King EA, Orandi B et al. Frailty, Mycophenolate Reduction, and Graft Loss in Kidney Transplant Recipients. Transplantation 2014

  30. Yao X, Hamilton RG, Weng NP, Xue QL, Bream JH, Li H, et al. Frailty is associated with impairment of vaccine-induced antibody response and increase in post-vaccination influenza infection in community-dwelling older adults. Vaccine. 2011;29(31):5015–21.

    Article  PubMed Central  PubMed  Google Scholar 

  31. Ridda I, Macintyre CR, Lindley R, Gao Z, Sullivan JS, Yuan FF, et al. Immunological responses to pneumococcal vaccine in frail older people. Vaccine. 2009;27(10):1628–36.

    Article  CAS  PubMed  Google Scholar 

  32. Fahey JL, Taylor JMG, Detels R, Hofmann B, Melmed R, Nishanian P, et al. The prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1. N Engl J Med. 1990;322:166–72.

    Article  CAS  PubMed  Google Scholar 

  33. Lahdevirta J, Maury CPJ, Teppo A-M, Repo H. Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am J Med. 1988;85:289–91.

    Article  CAS  PubMed  Google Scholar 

  34. Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. NEJM. 1998;338:853–60.

    Article  PubMed  Google Scholar 

  35. Liu H, Lin X, Xu Y, Chen S, Shi J, Morisky D. Emerging HIV epidemic among older adults in Nanning China. AIDS Patient Care STDS. 2012;26:565–7.

    Article  PubMed Central  PubMed  Google Scholar 

  36. Hontelez JA, Lurie MN, Newell ML, Bakker R, Tanser F, Barnighausen T, et al. Ageing with HIV in South Africa. AIDS. 2011;25(13):1665–7.

    Article  PubMed  Google Scholar 

  37. High KP, Brennan-Ing M, Clifford DB, Cohen MH, Currier J, Deeks SG, et al. HIV and aging: state of knowledge and areas of critical need for research. A report to the NIH Office of AIDS Research by the HIV and Aging Working Group. J Acquir Immune Defic Syndr. 2012;60 Suppl 1:S1–18. This paper provides a consensus view of the research agenda on frailty and other aspects of aging in people living with HIV infection.

    Article  CAS  PubMed  Google Scholar 

  38. Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, et al. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis. 2011;53(11):1120–6.

    Article  PubMed  Google Scholar 

  39. Deeks SG. HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med. 2011;62:141–55. This is a thorough review of evidence linking inflammation with aging in people with and without HIV infection.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Desquilbet L, Jacobson L, Fried LP, Phair JP, Jamieson BD, Holloway M, et al. A frailty-related phenotype before HAART initiation as an independent risk factor for AIDS or death after HAART among HIV-infected men. J Gerontol A Biol Sci Med Sci. 2011;66A:1030–8. This paper provides evidene that a frailty-related phenotype independently predicted onset of AIDS or death in a cohort of men who have sex with men.

  41. Althoff KN, Jacobson LP, Cranston RD, Detels R, Phair JP, Li X, et al. Age, comorbidities and AIDS predict the frailty phenotype in men who have sex with men. J Gerontol A Biol Sci Med Sci. 2014;69A:189–98. This paper reports data on the prevalence of the frailty phenotype in men who have sex with men, as well as factors associated with the incidence of this phenotype.

    Article  PubMed Central  Google Scholar 

  42. Green M, Covinsky K, Astemborski J, Piggot D, Brown T, Leng S et al. The relationship of physical performance with HIV disease and mortality. AIDS 2014; 28.

  43. Onen NF, Agbebi A, Shacham E, Stamm KE, Onen AR, Overton ET. Frailty among HIV-infected persons in an urban outpatient care setting. J Infect. 2009;59(5):346–52.

    Article  PubMed  Google Scholar 

  44. Franceschi C, Bonafe M, Valensin S, Olivieri F, De LM, Ottaviani E, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244–54.

    Article  CAS  PubMed  Google Scholar 

  45. De Martinis M, Franceschi C, Monti D, Ginaldi L. Inflammation markers predicting frailty and mortality in the elderly. Exp Mol Pathol. 2006;80(3):219–27.

    Article  PubMed  Google Scholar 

  46. Roubenoff R, Parise H, Payette HA, Abad LW, D’Agostino R, Jacques PF, et al. Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study. Am J Med. 2003;115(6):429–35.

    Article  CAS  PubMed  Google Scholar 

  47. Leng S, Chaves P, Koenig K, Walston J. Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study. J Am Geriatr Soc. 2002;50(7):1268–71. This paper was the first reporting supportive evidence for chronic inflammation as indicated by elevated IL-6 levels in frailty in the geriatric population.

    Article  PubMed  Google Scholar 

  48. Walston J, McBurnie MA, Newman A, Tracy RP, Kop WJ, Hirsch CH, et al. Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study. Arch Intern Med. 2002;162(20):2333–41.

    Article  PubMed  Google Scholar 

  49. Schmaltz HN, Fried LP, Xue QL, Walston J, Leng SX, Semba RD. Chronic cytomegalovirus infection and inflammation are associated with prevalent frailty in community-dwelling older women. J Am Geriatr Soc. 2005;53(5):747–54.

    Article  PubMed  Google Scholar 

  50. Leng SX, Xue QL, Tian J, Walston JD, Fried LP. Inflammation and frailty in older women. J Am Geriatr Soc. 2007;55(6):864–71. This paper further describes chronic inflammation as indicated by both higher IL-6 levels and white blood cell counts in frailty in the geriatric population.

    Article  PubMed  Google Scholar 

  51. Hubbard RE, O’Mahony MS, Savva GM, Calver BL, Woodhouse KW. Inflammation and frailty measures in older people. J Cell Mol Med. 2009;13(9B):3103–9.

    Article  PubMed  Google Scholar 

  52. Collerton J, Martin-Ruiz C, Davies K, Hilkens CM, Isaacs J, Kolenda C, et al. Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: cross-sectional findings from the Newcastle 85+ Study. Mech Ageing Dev. 2012;133(6):456–66.

    Article  CAS  PubMed  Google Scholar 

  53. Leng SX, Xue QL, Tian J, Huang Y, Yeh SH, Fried LP. Associations of neutrophil and monocyte counts with frailty in community-dwelling disabled older women: results from the Women’s Health and Aging Studies I. Exp Gerontol. 2009;44(8):511–6.

    Article  PubMed  Google Scholar 

  54. Semba RD, Margolick JB, Leng S, Walston J, Ricks MO, Fried LP. T cell subsets and mortality in older community-dwelling women. Exp Gerontol. 2005;40:81–7.

    Article  CAS  PubMed  Google Scholar 

  55. De Fanis U, Wang GC, Fedarko NS, Walston JD, Casolaro V, Leng SX. T-lymphocytes expressing CC chemokine receptor-5 are increased in frail older adults. J Am Geriatr Soc. 2008;56(5):904–8.

    Article  PubMed Central  PubMed  Google Scholar 

  56. Loetscher P, Uguccioni M, Bordoli L, Baggiolini M, Moser B, Chizzolini C, et al. CCR5 is characteristic of Th1 lymphocytes. Nature. 1998;391(6665):344–5.

    Article  CAS  PubMed  Google Scholar 

  57. Leng SX, Yang H, Walston JD. Decreased cell proliferation and altered cytokine production in frail older adults. Aging Clin Exp Res. 2004;16(3):249–52.

    Article  CAS  PubMed  Google Scholar 

  58. Qu T, Walston JD, Yang H, Fedarko NS, Xue QL, Beamer BA, et al. Upregulated ex vivo expression of stress-responsive inflammatory pathway genes by LPS-challenged CD14(+) monocytes in frail older adults. Mech Ageing Dev. 2009;130(3):161–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Qu T, Yang H, Walston JD, Fedarko NS, Leng SX. Upregulated monocytic expression of CXC chemokine ligand 10 (CXCL-10) and its relationship with serum interleukin-6 levels in the syndrome of frailty. Cytokine. 2009;46(3):319–24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Leng SX, Tian X, Matteini A, Li H, Hughes J, Jain A, et al. IL-6-independent association of elevated serum neopterin levels with prevalent frailty in community-dwelling older adults. Age Ageing. 2011;40(4):475–81.

    Article  PubMed Central  PubMed  Google Scholar 

  61. Ferrucci L, Penninx BW, Volpato S, Harris TB, Bandeen-Roche K, Balfour J, et al. Change in muscle strength explains accelerated decline of physical function in older women with high interleukin-6 serum levels. J Am Geriatr Soc. 2002;50(12):1947–54.

    Article  PubMed  Google Scholar 

  62. Maggio M, Guralnik JM, Longo DL, Ferrucci L. Interleukin-6 in aging and chronic disease: a magnificent pathway. J Gerontol A Biol Sci Med Sci. 2006;61(6):575–84.

    Article  PubMed Central  PubMed  Google Scholar 

  63. Chaves PH, Semba RD, Leng SX, Woodman RC, Ferrucci L, Guralnik JM, et al. Impact of anemia and cardiovascular disease on frailty status of community-dwelling older women: the Women’s Health and Aging Studies I and II. J Gerontol A Biol Sci Med Sci. 2005;60(6):729–35.

    Article  PubMed  Google Scholar 

  64. Leng SX, Cappola AR, Andersen RE, Blackman MR, Koenig K, Blair M, et al. Serum levels of insulin-like growth factor-I (IGF-I) and dehydroepiandrosterone sulfate (DHEA-S), and their relationships with serum interleukin-6, in the geriatric syndrome of frailty. Aging Clin Exp Res. 2004;16(2):153–7.

    Article  CAS  PubMed  Google Scholar 

  65. Leng SX, Hung W, Cappola AR, Yu Q, Xue QL, Fried LP. White blood cell counts, insulin-like growth factor-1 levels, and frailty in community-dwelling older women. J Gerontol A Biol Sci Med Sci. 2009;64(4):499–502.

    Article  PubMed  Google Scholar 

  66. Lederman MM, Funderburg NT, Sekaly RP, Klatt NR, Hunt PW. Residual immune dysregulation syndrome in treated HIV infection. Adv Immunol. 2013;119:51–83. This paper reviews the mechanisms of immune activation that persists in people with well-treated HIV infection.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Regidor DL, Detels R, Breen EC, Widney DP, Jacobson LP, Palella F, et al. Effect of highly active antiretroviral therapy on biomarkers of B-lymphocyte activation and inflammation. AIDS. 2011;25(3):303–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Martin J, Volberding P. HIV and premature aging: a field still in its infancy. Ann Intern Med. 2010;153(7):477–9.

    Article  PubMed  Google Scholar 

  69. Shiels MS, Pfeiffer RM, Engels EA. Age at cancer diagnosis among persons with AIDS in the United States. Ann Intern Med. 2010;153(7):452–60. This paper shows the effect of underlying age distributions in estimating relative rates of cancer (and by implication any disease) in groups that are not the same age.

    Article  PubMed Central  PubMed  Google Scholar 

  70. Erlandson KM, Allshouse AA, Jankowski CM, Lee EJ, Rufner KM, Palmer BE, et al. Association of functional impairment with inflammation and immune activation in HIV type 1-infected adults receiving effective antiretroviral therapy. J Infect Dis. 2013;208(2):249–59. This is one of the few studies to examine inflammation and frailty in people with HIV infection.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Justice AC, Freiberg MS, Tracy R, Kuller L, Tate JP, Goetz MB, et al. 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. 2012;54:984–94.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Womack JA, Goulet JL, Gibert C, Brandt CA, Skanderson M, Gulanski B, et al. Physiologic frailty and fragility fracture in HIV-infected male veterans. Clin Infect Dis. 2013;56(10):1498–504.

    Article  PubMed Central  PubMed  Google Scholar 

  73. Wada NI, Jacobson LP, Margolick JB, Breen EB, Macatangay B, Penugonda S et al. The effect of HAART-induced HIV suppression on circulating markers of inflammation and immune activation. AIDS. In press. This paper shows the magnitude and time course of effects of HIV suppression on systemic inflammation.

  74. Margolick JB, Martinez-Maza O, Jacobson L, Lopez J, Li X, Phair J et al. Frailty and circulating markers of inflammation in HIV-infected and -uninfected men in the Multicenter AIDS Cohort Study (MACS). Presented at the 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, GA, March 2013, Abstract #800 . 2013. Ref Type: Abstract

  75. Looney RJ, Falsey A, CAMPBELL D, Torres A, Kolassa J, Brower C, et al. Role of cytomegalovirus in the T cell changes seen in elderly individuals. Clin Immunol. 1999;90(2):213–9.

    Article  CAS  PubMed  Google Scholar 

  76. Olsson J, Wikby A, Johansson B, Lofgren S, Nilsson BO, Ferguson FG. Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study. Mech Ageing Dev. 2000;121(1–3):187–201.

    CAS  PubMed  Google Scholar 

  77. Pawelec G, Akbar A, Caruso C, Solana R, Grubeck-Loebenstein B, Wikby A. Human immunosenescence: is it infectious? Immunol Rev. 2005;205:257–68.

    Article  CAS  PubMed  Google Scholar 

  78. Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ, et al. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol. 2002;169(4):1984–92.

    Article  CAS  PubMed  Google Scholar 

  79. Koch S, Larbi A, Ozcelik D, Solana R, Gouttefangeas C, Attig S, et al. Cytomegalovirus infection: a driving force in human T cell immunosenescence. Ann N Y Acad Sci. 2007;1114:23–35.

    Article  CAS  PubMed  Google Scholar 

  80. Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med. 2005;202(5):673–85. This is a study of the immune response to the entire CMV genome (!) in healthy CMV-seropositive donors.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  81. Naeger DM, Martin JN, Sinclair E, Hunt PW, Bangsberg DR, Hecht F, et al. Cytomegalovirus-specific T cells persist at very high levels during long-term antiretroviral treatment of HIV disease. PLoS One. 2010;5(1):e8886.

    Article  PubMed Central  PubMed  Google Scholar 

  82. Li H, Margolick JB, Bream JH, Nilles TL, Langan S, Bui HT, et al. Heterogeneity of CD4+ and CD8+ T-cell responses of cytomegalovirus in HIV-infected and -uninfected men who have sex with men. J Infect Dis. 2014;210:400–4.

    Article  CAS  PubMed  Google Scholar 

  83. Wang GC, Kao WH, Murakami P, Xue QL, Chiou RB, Detrick B, et al. Cytomegalovirus infection and the risk of mortality and frailty in older women: a prospective observational cohort study. Am J Epidemiol. 2010;171(10):1144–52.

    Article  PubMed Central  PubMed  Google Scholar 

  84. Mathei C, Vaes B, Wallemacq P, Degryse J. Associations between cytomegalovirus infection and functional impairment and frailty in the BELFRAIL Cohort. J Am Geriatr Soc. 2011;59(12):2201–8.

    Article  PubMed  Google Scholar 

  85. Vallejo AN, Hamel Jr DL, Mueller RG, Ives DG, Michel JJ, Boudreau RM, et al. NK-like T cells and plasma cytokines, but not anti-viral serology, define immune fingerprints of resilience and mild disability in exceptional aging. PLoS ONE. 2011;6(10):e26558.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Leng SX, Qu T, Semba RD, Yao X, Nilles T, Yang X, et al. Relationship between cytomegalovirus (CMV) IgG seropositivity, detectable CMV DNA peripheral monocytes, and CMV-specific CD8+ T-cells in older adults. Age (Dordr). 2011;33:607–14. This paper provides evidence that presence of detectable CMV DNA in monocytes is a better predictor of a sizable CMV response than presence of antibody to CMV.

    Article  Google Scholar 

  87. Leng SX, Li H, Xue QL, Tian J, Yang X, Ferrucci L, et al. Association of detectable cytomegalovirus (CMV) DNA in monocytes rather than positive CMV IgG serology with elevated neopterin levels in community-dwelling older adults. Exp Gerontol. 2011;46(8):679–84.

    PubMed Central  CAS  PubMed  Google Scholar 

  88. Li H, Weng P, Najarro K, Xue Q-L, Semba RD, Margolick JB, et al. Chronic CMV infection in older women: longitudinal comparisons of CMV DNA in peripheral monocytes, anti-CMV IgG titers, serum IL-6 levels, and CMV pp 65 (NLV)-specific CD8+ T-cell frequencies with twelve year follow-up. Exp Gerontol. 2013;54:84–9. In this study presence of CMV DNA in monocytes was associated with higher levels of serum IL-6, a marker that is one of the most closely associated with frailty and aging.

    Article  Google Scholar 

  89. Pathai S, Bajillan H, Landay AL, High KP. Is HIV a Model of Accelerated or Accentuated Aging? J Gerontol A Biol Sci Med Sci. 2013.

  90. Barrett L, Fowke KR, Grant MD. Cytomegalovirus, aging, and HIV: a perfect storm. AIDS Rev. 2012;14(3):159–67.

    PubMed  Google Scholar 

  91. Hunt PW, Martin JN, Sinclair E, Epling L, Teague J, Jacobson MA, et al. Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J Infect Dis. 2011;203(10):1474–83. This is a treatment trial in which an anti-CMV agent, valganciclovir, reduces CMV expression and some markers of cellular immune activation, particularly on CD8 T-cells.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Pass RF, Zhang C, Evans A, Simpson T, Andrews W, Huang ML, et al. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med. 2009;360(12):1191–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Griffiths PD, Stanton A, McCarrell E, Smith C, Osman M, Harber M, et al. Cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant in transplant recipients: a phase 2 randomised placebo-controlled trial. Lancet. 2011;377(9773):1256–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  94. Sabbaj S, Pass RF, Goepfert PA, Pichon S. Glycoprotein B vaccine is capable of boosting both antibody and CD4 T-cell responses to cytomegalovirus in chronically infected women. J Infect Dis. 2011;203(11):1534–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  95. Kharfan-Dabaja MA, Boeckh M, Wilck MB, Langston AA, Chu AH, Wloch MK, et al. A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis. 2012;12(4):290–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by NIH grants U01AI35042 (Dr. Margolick), R21AG043874 (Dr. Leng), and R01AI108907 (Dr. Leng) and by funding from the Irma and Paul Milstein Program for Senior Health of the Milstein Medical Asian American Partnership (MMAAP) Foundation (www.mmaapf.org) (Dr. Leng).

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Sean X. Leng and Joseph B. Margolick declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, John R. Burton Pavilion, 5505 Hopkins Bayview Circle, Baltimore, MD, 21224, USA

    Sean X. Leng

  2. Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Room E5153, Baltimore, MD, 21205, USA

    Joseph B. Margolick

Authors
  1. Sean X. Leng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph B. Margolick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sean X. Leng or Joseph B. Margolick.

Additional information

This article is part of the Topical Collection on HIV Pathogenesis and Treatment

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Leng, S.X., Margolick, J.B. Understanding Frailty, Aging, and Inflammation in HIV Infection. Curr HIV/AIDS Rep 12, 25–32 (2015). https://doi.org/10.1007/s11904-014-0247-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11904-014-0247-3

Keywords

Search

Navigation