European Geriatric Medicine

, Volume 10, Issue 2, pp 175–182 | Cite as

Biomarkers of aging in HIV: inflammation and the microbiome

  • Camilla TincatiEmail author
  • Esther Merlini
  • Giuseppe Ancona
  • Giulia Marchetti



HIV-infected subjects present increased levels of inflammatory cytokines and T cell activation in the peripheral blood despite suppressive combination antiretroviral therapy which renders them susceptible to premature aging. The purpose of the present work was to review existing evidence on the ways in which the anatomical and microbiological abnormalities of the gastrointestinal tract can represent a major cause of organ disease in HIV infection.


We conducted a systematic review of the Pubmed database for articles published from 2014 to 2018. We included studies on inflammatory/activation biomarkers associated with cardiovascular and bone disease, neurocognitive impairment and serious non-AIDS events in HIV-infected subjects. We also included researches which linked peripheral inflammation/activation to the anatomical, immune and microbiological alterations of the gastrointestinal tract.


Recent literature data confirm the association between non-infectious comorbidities and inflammation in HIV infection which may be driven by gastrointestinal tract abnormalities, specifically microbial translocation and dysbiosis. Furthermore, there is mounting evidence on the possible role of metabolic functions of the microbiota in the pathogenesis of premature aging in the HIV-infected population.


Biomarkers need to be validated for their use in the management of HIV infection. Compounds which counteract microbial translocation, inflammation and dysbiosis have been investigated as alternative therapeutic strategies in viro-suppressed HIV-infected individuals, but appear to have limited efficacy, probably due to the multifactorial pathogenesis of non-infectious comorbidities in this setting.


HIV Inflammation Comorbidities Microbial translocation Microbiome Metabolome 



This work was supported by the Italian Ministry of Health, Regione Lombardia, grant “Giovani Ricercatori” (number GR-2009-1592029; PI: GM) and grant “Ricerca Finalizzata-Progetti di Rete” (number NET-2013-02355333-3; PI: GM).

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical approval

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

Informed consent

For this type of study, informed consent is not required.


  1. 1.
    Klatt NR, Chomont N, Douek DC, Deeks SG (2013) Immune activation and HIV persistence: implications for curative approaches to HIV infection. Immunol Rev 254:326–342CrossRefGoogle Scholar
  2. 2.
    Palella FJ, Delaney KM, Moorman AC et al (1998) Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 338:853–860CrossRefGoogle Scholar
  3. 3.
    Tsoukas C (2014) Immunosenescence and aging in HIV. Curr Opin HIV AIDS 9:398–404CrossRefGoogle Scholar
  4. 4.
    Steele AK, Lee EJ, Vestal B et al (2014) Contribution of intestinal barrier damage, microbial translocation and HIV-1 infection status to an inflammaging signature. PLoS One 9:e97171CrossRefGoogle Scholar
  5. 5.
    Duffau P, Ozanne A, Bonnet F et al (2018) Multimorbidity, age-related comorbidities and mortality: association of activation, senescence and inflammation markers in HIV adults. AIDS 32:1651–1660CrossRefGoogle Scholar
  6. 6.
    Justice AC, Erlandson KM, Hunt PW, Landay A, Miotti P, Tracy RP (2018) Can biomarkers advance HIV research and care in the antiretroviral therapy era? J Infect Dis 217:521–528CrossRefGoogle Scholar
  7. 7.
    Brenchley JM, Price DA, Schacker TW et al (2006) Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12:1365–1371CrossRefGoogle Scholar
  8. 8.
    Jiang W, Lederman MM, Hunt P et al (2009) 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 199:1177–1185CrossRefGoogle Scholar
  9. 9.
    Marchetti G, Bellistrì GM, Borghi E et al (2008) Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy. AIDS 22:2035–2038CrossRefGoogle Scholar
  10. 10.
    Longenecker CT, Sullivan C, Baker JV (2016) Immune activation and cardiovascular disease in chronic HIV infection. Curr Opin HIV AIDS 11:216–225CrossRefGoogle Scholar
  11. 11.
    Pedersen KK, Pedersen M, Trøseid M et al (2013) Microbial translocation in HIV infection is associated with dyslipidemia, insulin resistance, and risk of myocardial infarction. J Acquir Immune Defic Syndr 64:425–433CrossRefGoogle Scholar
  12. 12.
    Alcaide ML, Parmigiani A, Pallikkuth S et al (2013) Immune activation in HIV-infected aging women on antiretrovirals–implications for age-associated comorbidities: a cross-sectional pilot study. PLoS One 8:e63804CrossRefGoogle Scholar
  13. 13.
    Timmons T, Shen C, Aldrovandi G et al (2014) Microbial translocation and metabolic and body composition measures in treated and untreated HIV infection. AIDS Res Hum Retrovir 30:272–277CrossRefGoogle Scholar
  14. 14.
    Pedersen KK, Manner IW, Seljeflot I et al (2014) Monocyte activation, but not microbial translocation, is independently associated with markers of endovascular dysfunction in HIV-infected patients receiving cART. J Acquir Immune Defic Syndr 67:370–374CrossRefGoogle Scholar
  15. 15.
    Mooney S, Tracy R, Osler T, Grace C (2015) Elevated biomarkers of inflammation and coagulation in patients with HIV are associated with higher framingham and VACS Risk Index Scores. PLoS One 10:e0144312CrossRefGoogle Scholar
  16. 16.
    Bahrami H, Budoff M, Haberlen SA et al (2016) Inflammatory markers associated with subclinical coronary artery disease: the multicenter AIDS Cohort Study. J Am Heart Assoc 5:e003371CrossRefGoogle Scholar
  17. 17.
    Hsu DC, Ma YF, Hur S et al (2016) Plasma IL-6 levels are independently associated with atherosclerosis and mortality in HIV-infected individuals on suppressive antiretroviral therapy. AIDS 30:2065–2074CrossRefGoogle Scholar
  18. 18.
    McKibben RA, Margolick JB, Grinspoon S et al (2015) Elevated levels of monocyte activation markers are associated with subclinical atherosclerosis in men with and those without HIV infection. J Infect Dis 211:1219–1228CrossRefGoogle Scholar
  19. 19.
    Longenecker CT, Jiang Y, Orringer CE et al (2014) Soluble CD14 is independently associated with coronary calcification and extent of subclinical vascular disease in treated HIV infection. AIDS 28:969–977CrossRefGoogle Scholar
  20. 20.
    Hanna DB, Lin J, Post WS et al (2017) Association of macrophage inflammation biomarkers with progression of subclinical carotid artery atherosclerosis in HIV-infected women and men. J Infect Dis 215:1352–1361CrossRefGoogle Scholar
  21. 21.
    McGinty T, Mirmonsef P, Mallon PW, Landay AL (2016) Does systemic inflammation and immune activation contribute to fracture risk in HIV? Curr Opin HIV AIDS 11:253–260CrossRefGoogle Scholar
  22. 22.
    Ofotokun I, Titanji K, Vikulina T et al (2015) Role of T-cell reconstitution in HIV-1 antiretroviral therapy-induced bone loss. Nat Commun 6:8282CrossRefGoogle Scholar
  23. 23.
    Ofotokun I, Titanji K, Vunnava A et al (2016) Antiretroviral therapy induces a rapid increase in bone resorption that is positively associated with the magnitude of immune reconstitution in HIV infection. AIDS 30:405–414CrossRefGoogle Scholar
  24. 24.
    Titanji K, Vunnava A, Sheth AN et al (2014) Dysregulated B cell expression of RANKL and OPG correlates with loss of bone mineral density in HIV infection. PLoS Pathog 10:e1004497CrossRefGoogle Scholar
  25. 25.
    Hileman CO, Labbato DE, Storer NJ, Tangpricha V, McComsey GA (2014) Is bone loss linked to chronic inflammation in antiretroviral-naive HIV-infected adults? A 48-week matched cohort study. AIDS 28:1759–1767CrossRefGoogle Scholar
  26. 26.
    Manavalan JS, Arpadi S, Tharmarajah S et al (2016) Abnormal bone acquisition with early-life HIV infection: role of immune activation and senescent osteogenic precursors. J Bone Miner Res 31:1988–1996CrossRefGoogle Scholar
  27. 27.
    Tincati C, Basilissi M, Sinigaglia E et al (2014) Invariant natural killer T (iNKT) cells in HAART-treated, HIV-positive patients with bone and cardiovascular impairment. PLoS One 9:e110287CrossRefGoogle Scholar
  28. 28.
    D’Abramo A, Zingaropoli MA, Oliva A et al (2016) Higher levels of osteoprotegerin and immune activation/immunosenescence markers are correlated with concomitant bone and endovascular damage in HIV-suppressed patients. PLoS One 11:e0149601CrossRefGoogle Scholar
  29. 29.
    Erlandson KM, O’Riordan M, Labbato D, McComsey GA (2014) Relationships between inflammation, immune activation, and bone health among HIV-infected adults on stable antiretroviral therapy. J Acquir Immune Defic Syndr 65:290–298CrossRefGoogle Scholar
  30. 30.
    Kendall MA, Tassiopoulos K, McComsey GA, Yin MT (2015) Fractures are not associated with CD8(+) T cell activation: an analysis of the ACTG ALLRT Study. AIDS Res Hum Retrovir 31:769–771CrossRefGoogle Scholar
  31. 31.
    Rubin LH, Sacktor N, Creighton J et al (2018) Microglial activation is inversely associated with cognition in individuals living with HIV on effective antiretroviral therapy. AIDS 32:1661–1667CrossRefGoogle Scholar
  32. 32.
    D’Antoni ML, Byron MM, Chan P et al (2018) Normalization of soluble CD163 levels after institution of antiretroviral therapy during acute HIV infection tracks with fewer neurological abnormalities. J Infect Dis 218:1453–1463CrossRefGoogle Scholar
  33. 33.
    Hsu DC, Sunyakumthorn P, Wegner M, et al (2018) Central nervous system inflammation and infection during early, nonaccelerated simian-human immunodeficiency virus infection in Rhesus Macaques. J Virol 92Google Scholar
  34. 34.
    Kessing CF, Spudich S, Valcour V et al (2017) High number of activated CD8+ T cells targeting HIV antigens are present in cerebrospinal fluid in acute HIV infection. J Acquir Immune Defic Syndr 75:108–117CrossRefGoogle Scholar
  35. 35.
    Edén A, Marcotte TD, Heaton RK et al (2016) Increased intrathecal immune activation in virally suppressed HIV-1 infected patients with neurocognitive impairment. PLoS One 11:e0157160CrossRefGoogle Scholar
  36. 36.
    Montoya JL, Campbell LM, Paolillo EW, et al (2018) Inflammation relates to poorer complex motor performance among adults living with HIV on suppressive antiretroviral therapy. J Acquir Immune Defic SyndrGoogle Scholar
  37. 37.
    Jespersen S, Pedersen KK, Anesten B et al (2016) Soluble CD14 in cerebrospinal fluid is associated with markers of inflammation and axonal damage in untreated HIV-infected patients: a retrospective cross-sectional study. BMC Infect Dis 16:176CrossRefGoogle Scholar
  38. 38.
    Ulfhammer G, Edén A, Mellgren Å et al (2018) Persistent central nervous system immune activation following more than 10 years of effective HIV antiretroviral treatment. AIDS 32:2171–2178CrossRefGoogle Scholar
  39. 39.
    Pérez-Santiago J, De Oliveira MF, Var SR et al (2017) Increased cell-free mitochondrial DNA is a marker of ongoing inflammation and better neurocognitive function in virologically suppressed HIV-infected individuals. J Neurovirol 23:283–289CrossRefGoogle Scholar
  40. 40.
    Marchetti G, Cozzi-Lepri A, Merlini E et al (2011) Microbial translocation predicts disease progression of HIV-infected antiretroviral-naive patients with high CD4+ cell count. AIDS 25:1385–1394CrossRefGoogle Scholar
  41. 41.
    Sandler NG, Wand H, Roque A et al (2011) Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis 203:780–790CrossRefGoogle Scholar
  42. 42.
    Grund B, Baker JV, Deeks SG et al (2016) Relevance of Interleukin-6 and d-Dimer for serious non-AIDS morbidity and death among HIV-positive adults on suppressive antiretroviral therapy. PLoS One 11:e0155100CrossRefGoogle Scholar
  43. 43.
    Freiberg MS, Bebu I, Tracy R et al (2016) d-Dimer levels before HIV seroconversion remain elevated even after viral suppression and are associated with an increased risk of non-AIDS events. PLoS One 11:e0152588CrossRefGoogle Scholar
  44. 44.
    Nordell AD, McKenna M, Borges Á et al (2014) Severity of cardiovascular disease outcomes among patients with HIV is related to markers of inflammation and coagulation. J Am Heart Assoc 3:e000844CrossRefGoogle Scholar
  45. 45.
    McComsey GA, Kitch D, Sax PE et al (2014) Associations of inflammatory markers with AIDS and non-AIDS clinical events after initiation of antiretroviral therapy: AIDS clinical trials group A5224s, a substudy of ACTG A5202. J Acquir Immune Defic Syndr 65:167–174CrossRefGoogle Scholar
  46. 46.
    Tincati C, Douek DC, Marchetti G (2016) Gut barrier structure, mucosal immunity and intestinal microbiota in the pathogenesis and treatment of HIV infection. AIDS Res Ther 13:19CrossRefGoogle Scholar
  47. 47.
    Nazli A, Chan O, Dobson-Belaire WN et al (2010) Exposure to HIV-1 directly impairs mucosal epithelial barrier integrity allowing microbial translocation. PLoS Pathog 6:e1000852CrossRefGoogle Scholar
  48. 48.
    Perkins MR, Bartha I, Timmer JK et al (2015) The interplay between host genetic variation, viral replication, and microbial translocation in untreated HIV-infected individuals. J Infect Dis 212:578–584CrossRefGoogle Scholar
  49. 49.
    Chung CY, Alden SL, Fundburg NT, Fu P, Levine AD (2014) Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals. PLoS Pathog 10:e1004198CrossRefGoogle Scholar
  50. 50.
    Somsouk M, Estes JD, Deleage C et al (2015) Gut epithelial barrier and systemic inflammation during chronic HIV infection. AIDS 29:43–51CrossRefGoogle Scholar
  51. 51.
    Tincati C, Merlini E, Braidotti P et al (2016) Impaired gut junctional complexes feature late-treated individuals with suboptimal CD4+ T-cell recovery upon virologically suppressive combination antiretroviral therapy. AIDS 30:991–1003CrossRefGoogle Scholar
  52. 52.
    Hunt PW, Sinclair E, Rodriguez B et al (2014) Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection. J Infect Dis 210:1228–1238CrossRefGoogle Scholar
  53. 53.
    Chamoun MN, Blumenthal A, Sullivan MJ, Schembri MA, Ulett GC (2018) Bacterial pathogenesis and interleukin-17: interconnecting mechanisms of immune regulation, host genetics, and microbial virulence that influence severity of infection. Crit Rev Microbiol 44:465–486CrossRefGoogle Scholar
  54. 54.
    Song X, Dai D, He X et al (2015) Growth factor FGF2 cooperates with Interleukin-17 to repair intestinal epithelial damage. Immunity 43:488–501CrossRefGoogle Scholar
  55. 55.
    Lee JS, Tato CM, Joyce-Shaikh B et al (2015) Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 43:727–738CrossRefGoogle Scholar
  56. 56.
    Maxwell JR, Zhang Y, Brown WA et al (2015) Differential roles for Interleukin-23 and Interleukin-17 in intestinal immunoregulation. Immunity 43:739–750CrossRefGoogle Scholar
  57. 57.
    Mudd JC, Brenchley JM (2016) Gut mucosal barrier dysfunction, microbial dysbiosis, and their role in HIV-1 disease progression. J Infect Dis 214(Suppl 2):S58–S66CrossRefGoogle Scholar
  58. 58.
    Mudd JC, Brenchley JM (2016) ILC you later: early and irreparable loss of innate lymphocytes in HIV infection. Immunity 44:216–218CrossRefGoogle Scholar
  59. 59.
    Vujkovic-Cvijin I, Dunham RM, Iwai S et al (2013) Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci Transl Med 5:193ra91CrossRefGoogle Scholar
  60. 60.
    Gori A, Tincati C, Rizzardini G et al (2008) Early impairment of gut function and gut flora supporting a role for alteration of gastrointestinal mucosa in human immunodeficiency virus pathogenesis. J Clin Microbiol 46:757–758CrossRefGoogle Scholar
  61. 61.
    Dillon SM, Lee EJ, Kotter CV et al (2014) An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia. Mucosal Immunol 7:983–994CrossRefGoogle Scholar
  62. 62.
    Mutlu EA, Keshavarzian A, Losurdo J et al (2014) A compositional look at the human gastrointestinal microbiome and immune activation parameters in HIV infected subjects. PLoS Pathog 10:e1003829CrossRefGoogle Scholar
  63. 63.
    Vázquez-Castellanos JF, Serrano-Villar S, Latorre A et al (2015) Altered metabolism of gut microbiota contributes to chronic immune activation in HIV-infected individuals. Mucosal Immunol 8:760–772CrossRefGoogle Scholar
  64. 64.
    Lozupone CA, Li M, Campbell TB et al (2013) Alterations in the gut microbiota associated with HIV-1 infection. Cell Host Microbe 14:329–339CrossRefGoogle Scholar
  65. 65.
    Villanueva-Millán MJ, Pérez-Matute P, Recio-Fernández E, Lezana Rosales JM, Oteo JA (2017) Differential effects of antiretrovirals on microbial translocation and gut microbiota composition of HIV-infected patients. J Int AIDS Soc 20:21526CrossRefGoogle Scholar
  66. 66.
    Neff CP, Krueger O, Xiong K et al (2018) Fecal microbiota composition drives immune activation in HIV-infected individuals. EBioMedicine 30:192–202CrossRefGoogle Scholar
  67. 67.
    Serrano-Villar S, Moreno S, Ferrer M (2018) The functional consequences of the microbiome in HIV: insights from metabolomic studies. Curr Opin HIV AIDS 13:88–94CrossRefGoogle Scholar
  68. 68.
    McHardy IH, Li X, Tong M et al (2013) HIV Infection is associated with compositional and functional shifts in the rectal mucosal microbiota. Microbiome 1:26CrossRefGoogle Scholar
  69. 69.
    Serrano-Villar S, Rojo D, Martínez-Martínez M et al (2016) Gut bacteria metabolism impacts immune recovery in HIV-infected individuals. EBioMedicine 8:203–216CrossRefGoogle Scholar
  70. 70.
    Vujkovic-Cvijin I, Swainson LA, Chu SN et al (2015) Gut-resident Lactobacillus abundance associates with IDO1 inhibition and Th17 dynamics in SIV-infected macaques. Cell Rep 13:1589–1597CrossRefGoogle Scholar
  71. 71.
    Serrano-Villar S, Rojo D, Martínez-Martínez M et al (2016) HIV infection results in metabolic alterations in the gut microbiota different from those induced by other diseases. Sci Rep 6:26192CrossRefGoogle Scholar
  72. 72.
    Tenorio AR, Zheng Y, Bosch RJ et al (2014) Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment. J Infect Dis 210:1248–1259CrossRefGoogle Scholar
  73. 73.
    Srinivasa S, Fitch KV, Lo J et al (2015) Plaque burden in HIV-infected patients is associated with serum intestinal microbiota-generated trimethylamine. AIDS 29:443–452CrossRefGoogle Scholar
  74. 74.
    Shan Z, Clish CB, Hua S et al (2018) Gut microbial-related choline metabolite trimethylamine-N-oxide is associated with progression of carotid artery atherosclerosis in HIV infection. J Infect Dis 218:1474–1479CrossRefGoogle Scholar
  75. 75.
    Haissman JM, Knudsen A, Hoel H et al (2016) Microbiota-dependent marker TMAO is elevated in silent ischemia but is not associated with first-time myocardial infarction in HIV infection. J Acquir Immune Defic Syndr 71:130–136CrossRefGoogle Scholar
  76. 76.
    Miller PE, Haberlen SA, Brown TT et al (2016) Brief report: intestinal microbiota-produced trimethylamine-N-oxide and its association with coronary stenosis and HIV serostatus. J Acquir Immune Defic Syndr 72:114–118CrossRefGoogle Scholar
  77. 77.
    Haissman JM, Haugaard AK, Ostrowski SR et al (2017) Microbiota-dependent metabolite and cardiovascular disease marker trimethylamine-N-oxide (TMAO) is associated with monocyte activation but not platelet function in untreated HIV infection. BMC Infect Dis 17:445CrossRefGoogle Scholar
  78. 78.
    Missailidis C, Neogi U, Stenvinkel P, Trøseid M, Nowak P, Bergman P (2018) The microbial metabolite trimethylamine-N-oxide in association with inflammation and microbial dysregulation in three HIV cohorts at various disease stages. AIDS 32:1589–1598CrossRefGoogle Scholar
  79. 79.
    Carabotti M, Scirocco A, Maselli MA, Severi C (2015) The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol 28:203–209Google Scholar
  80. 80.
    Alakkas A, Ellis RJ, Watson CW et al (2018) White matter damage, neuroinflammation, and neuronal integrity in HAND. J NeurovirolGoogle Scholar
  81. 81.
    McGinty T, Mallon PWG (2018) Fractures and the gut microbiome. Curr Opin HIV AIDS 13:28–37CrossRefGoogle Scholar
  82. 82.
    Serrano-Villar S, de Lagarde M, Vázquez-Castellanos J et al (2018) Effects of immunonutrition in advanced HIV disease: a randomized placebo controlled clinical trial (Promaltia study). Clin Infect DisGoogle Scholar
  83. 83.
    Sunil M, Nigalye M, Somasunderam A et al (2016) Unchanged levels of soluble CD14 and IL-6 over time predict serious non-AIDS events in HIV-1-infected people. AIDS Res Hum Retrovir 32:1205–1209CrossRefGoogle Scholar

Copyright information

© European Geriatric Medicine Society 2018

Authors and Affiliations

  1. 1.Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, San Paolo HospitalUniversity of MilanMilanItaly

Personalised recommendations