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HIV Induced Aging of the Immune System

HIV Induced Aging of the Immune System. Dr. Tammy Rickabaugh February 4, 2013. Overview. Immunological Aging in Seronegative Individuals Premature Aging of the Immune System in HIV-1 + Individuals: Is this the cause of AIDS?

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HIV Induced Aging of the Immune System

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  1. HIV Induced Aging of the Immune System Dr. Tammy Rickabaugh February 4, 2013

  2. Overview • Immunological Aging in Seronegative Individuals • Premature Aging of the Immune System in HIV-1+ Individuals: Is this the cause of AIDS? • Implications of Premature Immunological Aging of HIV-1+ Individuals

  3. Immunological Aging in Seronegative Individuals

  4. General Concepts of Aging Kovaiou, Grubeck-Loebenstien, 2006

  5. Age-Associated Changes in the Immune System • Elderly people are more susceptible to infections • Less protected by vaccines • Infections in the elderly are characterized by more severe symptoms, longer duration, and poorer prognosis • Reactivation of Varicella-Zoster, risks for pneumonia, urinary tract infections, meningitis, TB and viral gastroenteritis • Related to age-related changes in the immune system

  6. Jamieson, BD, et al, Immunity, 1999 The Human Thymus Involutes With Age Fetal Thymus Adult Thymus

  7. Age-Associated Changes in CD4+ T Cells • Significant decrease in naïve T cell number and increase in memory T cells -hinders ability to respond to new infections • Diversity of the naïve CD4+ T cell compartment is maintained until about 70 years of age -a dramatic and sudden collapse of diversity occurs -less diversity in T cell receptor, hinders ability to respond to new antigens

  8. Age-Associated Changes in CD4+ T Cells • Using cell surface markers normally used to identify naïve T cells is difficult - “naïve” cells in the elderly express receptors and functional abilities more like memory cells • Signaling and cytokine secretion in naïve CD4+ T cells is altered and the activation potential of memory cells is also decreased -hinders ability to mount effective immune responses to antigens

  9. Model for CD4+ T Cell Differentiation During Healthy Aging Kovaiou, Grubeck-Loebenstien, 2006

  10. Summary of Age-Related Changes Within the CD4+ T Cells Kovaiou, Grubeck-Loebenstien, 2006

  11. Summary of Age-related Changes Within the CD8+ T Cells • Increase in terminally differentiated cells • Decrease in naïve CD8+ T cells • See an increase in Type 1 (IL-2, IFN-g,TNF-a) and Type 2 (IL-4, IL-6, IL-10) cells- associated with chronic pro-inflammatory status • Increase in clonal expansions • Decrease in T cell receptor diversity • Shortening of telomere length

  12. What are the implications of increased numbers of senescent T-cells???

  13. Why Do Senescent Cells Accumulate With Age? • One main reason is an age-related decrease in apoptosis • Apoptosis is necessary to create “immunological space” for naïve cells to inhabit • This is more prominent in CD8+ T-cells • Senescent cells are not susceptible to normal death signals

  14. T-cells Become Resistant to Activation-Induced Cell Death (AICD) -Happens at a stage prior to complete senescence -AICD is a mechanism to prevent the expansion of unwanted T-cells Mountz, JD, et al. Immunological Reviews, 2005

  15. Increase in Senescent Cells Occupying “Immunological Space” Results in a Decrease in the Virus-Specific CTL Response -This can also contribute to “inflammaging” Mountz, JD, et al. Immunological Reviews, 2005

  16. Consequences of “Inflammaging” • In aging there is a profound modification in the cytokine network • General increase in the levels of pro-inflammatory cytokines • Chronic low grade pro-inflammatory condition is called “inflammaging”

  17. Inflammaging can trigger the following conditions: Franceschi, C., et al., Neuroimmunomodulation, 2008

  18. Some of our data…….

  19. The Proportion of Naïve T-cells Decreases Only Moderately Throughout Adulthood CD4+ CD45RA+ 100 90 80 70 60 % of CD4+ T-cells Expressing CD45RA 50 40 30 20 10 0 20 25 30 35 40 45 50 55 60 Participant Age

  20. Naive 8% 48% CD31 14% CD45RA Four CD4+ T-cell Subsets Defined by CD45RA and CD31 RA+31+ Least Differentiated TREC High Differentiated RA+31- TREC Low

  21. Maintenance of Naïve CD4+ T-cells During Aging Is Due To Stability of CD45RA+CD31- Subset Cross Sectional Study 60 50 40 % CD45RA+CD31+ cells 31+ 30 20 10 0 20 30 40 50 60 ParticipantAge (Years) p=0.38 60 50 40 30 31- % CD45RA+CD31- cells 20 10 0 20 30 40 50 60 ParticipantAge (Years) Kilpatrick, R, Rickabaugh, T, et. al, J. Immunology, 2008

  22. Telomeres • Hallmark of cellular aging • Region of repetitive DNA at the ends of chromosomes • Protects the end of chromosome from damage -similar to tips on shoelaces that keep it from unraveling -shortens with each replication of the cell • Telomere shortening in humans can result in senescence (cells lose the ability to divide) and block cell division • Cells have a limited capacity to replicate and this appears to be partly determined by telomere length

  23. Telomeres Human chromosome is gray and telomeres are the white dots

  24. Evidence of Telomere Shortening in Naïve CD4+ T cells with Age Kilpatrick, R, Rickabaugh, T, et. al, J. Immunology, 2008

  25. WITH AGE Model of CD4+ T-cellDifferentiation Thymus Homeostatic Proliferation CD45RA- Memory Antigen CD45RA+CD31- CD45RA+CD31+ LeastDifferentiated Naïve Differentiated Naive • We observe telomere shortening in both subsets with age

  26. Premature Aging of the Immune System in HIV-1+ Individuals:Is This the Cause of AIDS?

  27. Some Causes of Clinical Immunodeficiency • Not completely clear why the immune system initially controls HIV-1 infection and then ultimately fails to control viral replication • Viral escape with mutations in epitopes recognized by cytotoxic T lymphocytes (CTLs) • Functional impairment of HIV-specific CTLs • High levels of immune activation

  28. HIV-specific CD8+ T cell response: Impaired or Fully Functional? • In primary HIV-1 infection there is a rapid expansion of HIV-specific effector CD8+ T cells -phenotypically the cells appear to be at an intermediate stage of differentiation -but they are fully functional • Why is the virus not cleared?? -the combination of CD4+ T cell depletion and immune escape may lead to an inability of the CD8+ T cells to respond to low levels of viral replication (around the set point) - fully functional but unable to mount an effective response

  29. HIV-1 Strategies to Evade Host Immunity Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002

  30. HIV-1 Strategies to Evade Host Immunity Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002

  31. The Adaptive Immune System in Aging and HIV-1 Infection Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002

  32. Parallels Between HIV-1 Pathogenesis and Human Aging • Lifespan of both CD4+ and CD8+ T cells is shortened to about a third of normal -increase of CD8+ T cells but CD4+ cannot keep up with the pace of destruction • Increase in the amount of terminally differentiated T cells- consequence of immune activation -leads to immunosenescence, also occurs with CMV -get an accumulation of immune cells that cannot function or replicate normally, but are more resistant to apoptosis • AIDS is much more severe immune senescence than what is seen in normal aging

  33. Post-Thymic Development of CD8+ and CD4+ T cells Appay, V and Rowland-Jones, SL, Trends in Immunology, 2002

  34. Accumulation of Terminally Differentiated T cells in HIV infection Appay, V, et al. Experimental Gerontology, 2007

  35. Exhaustion of Immune Resources by HIV-1 Leads to AIDS • Chronic Immune Activation: -In primary infection there is massive immune activation -In chronic infection still have chronic immune activation due to viral rebounds -Indirect immune activation as depletion of CD4+ T cells results in more common infections and opportunistic infections • This can result in premature aging of the immune system and exhaustion of immune resources

  36. Exhaustion of HIV-specific CD8+ T cell Clonal Populations Appay, V, et al. Experimental Gerontology, 2007

  37. Exhaustion of HIV-specific CD8+ T cell Clonal Populations Appay, V, et al. Experimental Gerontology, 2007

  38. Exhaustion of HIV-specific CD8+ T cell Clonal Populations Appay, V, et al. Experimental Gerontology, 2007

  39. Some of our own data regarding naïve CD4+ T cells…….

  40. Individuals Early in HIV Infection Have Significantly Fewer Naïve CD4+ T-cells Rickabaugh, TM, et al., PLoS ONE 2011

  41. HIV Infection Results in a Greater Loss of CD31- T-cells Rickabaugh, TM, et al., PLoS ONE 2011

  42. Naïve CD4+ T-cells of HIV Infected Men Have Shorter Telomere Lengths Rickabaugh, TM, et al., PLoS ONE2011

  43. CD31 Expression on CD4+ T-cells is Associated with Progression to AIDS * p=0.038 5000 4000 CD31 MFI 3000 2000 1000 0 Progressed to AIDS within > 5 years Progressed to AIDS within 1 year Cao, WW et al., J Acquir Immune Defic Syndr2008

  44. What is the Effect of HAART on Naïve CD4+ T-cells?

  45. Reconstitution by HAART Does Not Completely Restore the CD31- Naïve T-Cell Compartment Rickabaugh, TM, et al., PLoS ONE,2011

  46. CD31+/Hi T-cells Increase Significantly Post-HAART Rickabaugh, TM, et al., PLoS ONE,2011

  47. Seronegative 4-8 years 12-16 years Reconstitution of CD31+ T-cells appears to be better with more time on ART CD45RA+CD28+CD31+CD4+ 200 150 Absolute Cell Counts 100 50 0 20 30 40 50 60 70 Age at time of analysis

  48. 12-16 years Seronegative 4-8 years Time on ART does not appear to increase CD31- naïve CD4+ T-cells CD45RA+CD28+CD31-CD4+ 120 100 80 Absolute Cell Counts 60 40 20 20 30 40 50 60 70 Age at time of analysis

  49. Model of CD4+ T-cell Differentiation Thymus Homeostatic Proliferation CD45RA- Memory Antigen CD45RA+CD31- CD45RA+CD31+ Least Differentiated Naïve Differentiated Naive AGE HIV HIV AGE • We observe telomere shortening in both subsets with age and HIV

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