T‐cell immunosenescence is associated with the presence of Kaposi's sarcoma in antiretroviral treated human immunodeficiency virus infected persons P. Unemori*1, K.S.Leslie1, P.Hunt2, E.Sinclair2, R.Effros3, J.D. Dock3, R. Mitsuyasu3, J. Martin2, S. Deeks2, T.A. Maurer1. 1University of California‐San Francisco, Dermatology, San Francisco, USA. 2University of California‐San Francisco, Medicine, San Francisco, USA. 3University of California‐Los Angeles, Pathology, Los Angeles, USA. *No conflicts of interest Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA General Points, Outline • Background –Kaposi’s sarcoma (KS) • Atypical cohort KS and immunosenescence • Project Structure and Methods • Results –increased global markers of T cell immunosenenscence and decreased naïve T cells in atypical KS cohort • Conclusions, implications for aging, HIV, and malignancy Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA History of KS • Moritz Kaposi Austrian Dermatologist • 1872 ‐ Described “idiopathic multiple pigmented sarcoma,” older patients • KSHV or HHV8 Chang Y, et al. 1994 Science 1837‐1902 Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Clinical Types of KS • Classical • Endemic • HIV associated • Transplant Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA The Era of Antiretroviral Therapy Incidence of KS Introduction of ART “beacon” Low CD4 ART Immune system recovery ? KS resolution, decreased incidence Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Atypical KS Cohort ‐Lesions strikingly reminiscent of classical KS ‐Middle‐aged men ‐Well controlled HIV Why did KS develop in this immunorestored group? Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA KS and Immunosenescence • HIV associated KS ‐ usually seen in immune‐ challenged, low CD4 count patients • Classical KS – usually seen in the elderly • Is there a role for immunosencence in this atypical KS HIV infected cohort? Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA KS and Immunosenescence • Unique opportunity Examine potential interplay between immunosenescence, HIV, and an AIDS defining malignancy such as KS • Immunosenescence and KS sparse literature Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Immunosenescence Aging Immunosenescence ↑ Global Markers ‐↑CD28 null ‐↑ CD57 ?Tcell Dysfunction? ‐telomere ↓ Naïve T cells ↓ CD27/CD28/CD45RA Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Objective Compare global markers of immunosenescence (CD57+ and CD28-), naïve cell markers (CD27+CD28+CD45RA+), and telomere length in CD8+ and CD4+ T cells subsets of HIV+KS+ cases vs. HIV+KS- controls. Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Model Aging Immunosenescence ↑ Global Markers ‐↑CD28 null ‐↑ CD57 ‐telomere ?Tcell Dysfunction? KS ↓ Naïve T cells ↓ CD27/CD28/CD45RA HIV Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Hypotheses –KS and Immunosenescence Specific Hypotheses: 1) Percent CD57+ and CD28‐ cells will be increased in CD4 and CD8 compartments of HIV+KS+ cases vs. HIV+KS‐ controls 2) Naïve T cells (CD27+/CD28+/CD45RA+) and telomere length will be decreased in CD4 and CD8 compartments of HIV+KS+ cases vs. HIV+KS‐ controls Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Methods • Retrospective case‐control pilot study. • Recruitment –cases and controls HIV primary care practices San Francisco and adjacent counties. History and physical, peripheral blood collection. • Flow cytometric analyses –UCSF Core Immunology Laboratory, batched analyses. • Telomere length (Fauce, et al, J Immuno 2008). Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Inclusion Criteria • HIV+, CD4+ counts > 300/mm3 , viral load <75 copies/mL, sustained for 24 months prior to enrollment • Cases had active biopsy proven KS lesions • Controls did not have any KS in prior 24 months Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Exclusion Criteria • History of immunomodulatory or chemotherapy use within 1 year of enrollment • Current active treatment for Hepatitis C requiring interferon based therapy • Current other active malignancy • Women excluded due to potential gender effects on immune responses (Meier, Nat Med 2009) Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Subjects – Cases and Controls HIV+KS- Controls HIV+KS+ Cases (Median, Range) (Median, Range) Number of Subjects (N) 47 19 Age (years ) 43 (29-60)* 54 (39-74)* CD4 cell count (cells/mm3) 521 (311-1194) 701 (338-1205) CD8 cell count (cells/mm3) 1,200 (425-3485 933 (429-2543) Viral Load (copies/mL) <75 <75 *p<0.001 Values expressed as Median (range) -CD4, CD8 and Viral load not significantly different in cases vs. controls Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Results –%CD57+CD4+ T cells P=0.07* *Age‐adjusted P value Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Results ‐ %CD57+CD8+ T cells P=0.005* *Age‐adjusted P value Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Results ‐ %CD28‐CD4+ T cells P=0.03* *Age‐adjusted P value Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Results ‐ %CD28‐ in CD8 T cells P=0.044* *Age‐adjusted P value Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Results – %CD27+CD28+CD45RA+CD4+ T cells P=0.11* *Age‐adjusted P value Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Results ‐%CD27+CD28+CD45RA+CD8+ T cells P=0.022* *Age‐adjusted P value Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Result – Telomere length P>0.5* *Age‐adjusted P value Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Summary • Global markers of immunosenescence associated with presence of KS • Naïve T cells decreased in KS • No difference in telomere length Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Conclusions • Although telomere length was not different (power, PBMCs), evidence that KS, an AIDS defining malignancy, is associated with enduring HIV associated T cell dysfunction and immunosenescence • Supports model: HIV inflammation immune aging clinical sequelae • Implications for monitoring and long term management of our aging HIV+ populations Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA Acknowledgements • Study participants • Toby Maurer, MD • Kieron Leslie, MD • Peter Hunt, MD • Steve Deeks, MD • Jeff Martin, MD • Core Immunology Lab at UCSF, Lorrie Epling, Elizabeth Sinclair, PhD • UCLA: Rita Effros, PhD, Ronald Mitsuyasu, MD • UCSF Department of Dermatology, Maya Ponte, MD, Nicole Wellman, MD • UCSF SCOPE, Becky Hoh, Marcia Smith, Joy Madamba • UCSF Center for Translational Sciences Institute –Travel Grant • NIH P30AI045008‐09, University of Pennsylvania CFAR Presented at the 1st Int. workshop on HIV & Aging,4 – 5 Oct. 2010, Baltimore, USA.