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HIV DNA and RNA levels are higher in gut, but viral transcription is not commensurate

CD4+ T cell reconstitution, T cell activation, and memory T cell subset composition in blood and gut of HIV- and ART-suppressed HIV+ patients: implications for HIV persistence in the gut.

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HIV DNA and RNA levels are higher in gut, but viral transcription is not commensurate

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  1. CD4+ T cell reconstitution, T cell activation, and memory T cell subset composition in blood and gut of HIV- and ART-suppressed HIV+ patients: implications for HIV persistence in the gut Steven Yukl1,2, Elizabeth Sinclair2,3, Lorrie Epling2,3, Qingsheng Li4, Amandeep Shergill1,2, Kenneth McQuaid1,2, Lijie Duan4, C. Bradley Hare2,3, Harry Lampiris1,2, Ashley Haase4, Diane Havlir2,3, Joseph Wong1,2, PLUS Study Group 1. San Francisco VA Medical Center, CA, USA 2. University of California, San Francisco (UCSF), CA, USA 3. San Francisco General Hospital, CA, USA 4. University of Minnesota, Minneapolis, MN, USA

  2. HIV DNA and RNA levels are higher in gut, but viral transcription is not commensurate S Yukl et al, CROI 2010; in press, JID Transcriptional activity (RNA/DNA) is not commensurately high in the gut Ileum has the highest median RNA/DNA HIV DNA is 3 to 9x higher in the gut HIV RNA is 2 to 10x higher (not shown)

  3. The effects of raltegravir intensification are consistent with ongoing replication in the ileum but not other sites CD8+ T cell activation decreased in the ileum and blood (6 of 7pts) HIV RNA (unspliced) decreased only in terminal ileum (5 of 7 pts) CD4% increased only in the ileum (6 of 7) S Yukl et al, CROI 2010 submitted, AIDS

  4. Hypotheses 1. The ileum, which may be a site of ongoing replication in patients on ART, will have abnormal CD4+ T cell numbers and T cell activation relative to HIV- patients

  5. Hypotheses 1. The ileum, which may be a site of ongoing replication in patients on ART, will have abnormal CD4+ T cell numbers and T cell activation relative to HIV- patients 2. Disproportionately high levels of HIV in the gut (relative to blood) may reflect differences in the proportion of certain memory T cell subtypes (CM, TM) or in the frequency of infection of these subtypes

  6. Study Population and Assays 10 HIV+ patients on ART with undetectable plasma VL • 8 patients: duodenum, ileum, colon, rectum (9-10 bx /site) • 2 patients: ileum alone (15 bx) 8 age and sex-matched HIV- comparators Biopsies from ileum and/or rectum (4 bx/site)

  7. CD4+ T cell reconstitution is incomplete in the ileum but may be complete in the rectum By immunohistochemistry: ileal CD4 numbers appear normal in the lymphoid aggregates but not the lamina propria.

  8. T cell activation remains high in blood and both gut sites

  9. CD4+ T Cell Memory Subtypes Vary by HIV Status and Site

  10. CD4+ T Cell Memory Subtypes Vary by HIV Status and Site

  11. CD4+ T Cell Memory Subtypes Vary by HIV Status and Site

  12. CD4+ T Cell Memory Subtypes Vary by HIV Status and Site

  13. CD4+ T Cell Memory Subtypes Vary by HIV Status and Site

  14. HIV DNA Content Differs by Cell Type in Blood and Ileum ND=not detected Tentative: Ileal TM cells may have more HIV DNA (21x) than peripheral TM cells

  15. Results • In HIV+ patients, the ileum has low numbers of CD4+ T cells while the rectum does not • The ileum may have an abnormal distribution of CD4+ T cell subtypes • CD8+ T cell activation remains abnormally high high in the ileum as well as other sites • Compared to the blood, the ileum has a lower % of CM cells and a comparable % of TM cells • HIV DNA levels in ileal TM cells may be much higher than in peripheral TM cells (tentative)

  16. Conclusions • Abnormally high CD8+ T cell activation and abnormal CD4 reconstitution in the ileum are consistent with chronic virus production • High HIV levels in the ileum do not appear to be explained solely by the % of CM and TM cells, but may reflect an increased frequency of infection of TM cells

  17. Acknowledgments Collaborators: UCSF Core Immunology Lab Terence Ho Valerie Girling Lorrie Epling Elizabeth Sinclair University of Zurich Hospital Sara Gianella (now at UCSD) Huldrych Gunthard Marek Fischer University of Minnesota Lijie Duan Qingsheng Li Ashley Haase San Francisco DPH Mark Pandori The study participants! Mentors: Joseph Wong Diane Havlir Study Team: Michele Downing Harry Lampiris C. Bradley Hare Amandeep Shergill Kenneth McQuaid SFVAMC GI Procedures Unit Funding: Dept of Veterans Affairs National Institutes of Health UCSF CFAR

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