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Patients Selected : initiation of HAART during the study period

Women’s Interagency HIV Study (WIHS) Multicenter, prospective, longitudinal study of the natural history of HIV infection among women in the U.S. Patients Selected : initiation of HAART during the study period availability of both pre-HAART and post-HAART specimens

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Patients Selected : initiation of HAART during the study period

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  1. Women’s Interagency HIV Study (WIHS)Multicenter, prospective, longitudinal study of the natural history of HIV infection among women in the U.S. Patients Selected: • initiation of HAART during the study period • availability of both pre-HAART and post-HAART specimens • non-pregnant; not taking immunomodulatory therapy 237 HIV+ adult women Pre-HAARTMean Range Age (yrs) CD4 count (cells/ml) 300 0 - 1200 Viral Load (log) 4.4 1.9 - 6.8

  2. Women’s Interagency HIV Study (WIHS) Cross-sectional Analyses: • Are increased IL-7 levels associated with CD4 lymphopenia in women? • Are increased IL-7 associated with increased HIV-1 viral load in women? Longitudinal Analyses: • Do pre-HAART IL-7 levels predict the degree of immune reconstitution after HAART initiation? Do those with higher IL-7 levels achieve better immune reconstitution? • Do IL-7 levels decline with CD4 recovery?

  3. 1.0 Pre-HAART log IL-7 level 0.5 0.0 Rho = -0.62 p < 0.0001 1.0 1.5 2.0 2.5 3.0 Pre-HAART log CD4 cell count Circulating IL-7 levels are associated with CD4+ T cell lymphopenia Women’s Interagency HIV Study (WIHS) Cross-sectional analysis (n=231)

  4. Rho = 0.27 p = 0.0001 1.0 Pre-HAART log IL-7 level 0.5 0.0 2 3 4 5 6 Pre-HAART log HIV RNA level Circulating IL-7 levels are associated with increased HIV-1 viral load Women’s Interagency HIV Study (WIHS) Cross-sectional analysis (n=217)

  5. Rho = 0.36 p < 0.0001 1 0 Change in log CD4 cell counts (6-12 mos post-HAART) -1 -2 0 5 10 15 20 25 Pre-HAART IL-7 level Pre-HAART IL-7 levels predict CD4+ T cell recovery after HAART initiation Women’s Interagency HIV Study (WIHS), n=200

  6. Rho= -0.61 p < 0.0001 1 0 Change in log CD4 cell counts (6-12 mos post-HAART) -1 -2 -20 -10 0 10 20 30 Change in IL-7 level Post-HAART IL-7 levels decrease as CD4+ T cells recover Women’s Interagency HIV Study (WIHS)

  7. Conclusions 1.There is a strong and independent correlation between circulating IL-7 levels and CD4+ T lymphopenia in HIV-1-infected individuals • Given the proficiency of IL-7 to stimulate the production and expansion of T cells, we propose IL-7 levels are increased as part of a homeostatic response to HIV-1 mediated T cell depletion. • Our hypothesis is supported by the detection of elevated IL-7 levels in other lymphopenic conditions (e.g., severe combined immunodeficiency syndrome and acute lymphocytic leukemia) and by the normalization of IL-7 levels when lymphopenia resolves.

  8. Conclusions(continued) 2. IL-7 is produced by dendritic-like cells within peripheral lymph nodes • These cells may increase production of IL-7 after “sensing” T cell depletion. 3. IL-7 production is significantly increased within lymphocyte-depleted tissues • Depleted lymph nodes are characterized by • Increased percentage of IL-7 positive cells • Increased amount of IL-7 produced per cell • This supports our hypothesis that increased IL-7 production occurs in response to lymphocyte depletion.

  9. Conclusions(continued) 4. Pre-HAART IL-7 levels predict the degree of CD4+ T cell recovery in HIV-1 infected patients placed on HAART • Thus, increased IL-7 levels may function to increase lymphocyte production and/or expansion. These data support a homeostatic role for IL-7. • The association between IL-7 levels and immune recovery may not be evident in individuals with irreversible HIV-1 mediated destruction of thymus, bone marrow, or lymph nodes. 5. IL-7 levels decline with CD4+ T cell restoration

  10. Conclusions(continued) 6. Higher circulating levels of IL-7 are associated with increased HIV-1 viral load • Given the capacity of IL-7 to enhance HIV-1 replication in vitro, these data suggest that IL-7 may enhance HIV-1 replication in vivo and lead to increased viral burden and accelerated disease progression. 7. Our data support further investigation into the role of IL-7 in T cell homeostasis and into the role of IL-7 in the progression and treatment of HIV-1 disease

  11. Acknowledgments Mike McCune Gladstone Institute of Virology and Immunology Karolinska Institute Bob Grant ` Jan Andersson Trevor Burt Lena Radler Diane Schmidt Kaveh Bastani UCSF Mary Beth Hanley Steve Deeks Eric Wieder Brian Herndier Rick Loftus WIHS Bob Halvorsen Ruth Greenblatt Steven Gange Stanford University Yolanda Barron Lee Herzenberg Helen Durkin Steve DeRosa Mary Young Mardge Cohen Project Inform Kathryn Anastos Alexandra Levine Survive AIDS

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