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2014 “Towards an HIV Cure” symposium Melbourne

2014 “Towards an HIV Cure” symposium Melbourne. SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne. HIV persistence in the testis?. Does HIV persist in the testis? Why should we care? Transmission through seminal plasma?

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2014 “Towards an HIV Cure” symposium Melbourne

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  1. 2014 “Towards an HIV Cure” symposiumMelbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne

  2. HIV persistence in the testis? • Does HIV persist in the testis? • Why should we care? • Transmission through seminal plasma? • Reservoir during cART? ?

  3. Is the testis a sanctuary for HIV? • Possible mechanisms for HIV persistence in the testis: • Blood testis barrier? • Testicular immune privilege? ?

  4. Interstitium Seminiferous tubule Cells of the testis Lumen blood vessel lymphatic vessel

  5. Interstitium Seminiferous tubule Cells of the testis Lumen Spermatids blood vessel Spermatocytes lymphatic vessel Spermatogonia

  6. Interstitium Seminiferous tubule Cells of the testis Sertoli cells Lumen blood vessel lymphatic vessel

  7. Interstitium Seminiferous tubule Cells of the testis Sertoli cells Blood-testis barrier Lumen Pgp blood vessel lymphatic vessel

  8. Interstitium Seminiferous tubule Cells of the testis Sertoli cells Blood-testis barrier Lumen Pgp Leukocytes: macrophages T cells blood vessel lymphatic vessel Leydig cells

  9. Is the testis a sanctuary for HIV? • Possible mechanisms for HIV persistence in the testis: • Blood testis barrier? • Testicular immune privilege? ?

  10. Is the testis a sanctuary for HIV? • Possible mechanisms for HIV persistence in the testis: • Blood testis barrier? • Testicular immune privilege? • Suppression of innate and acquired immune responses in the testis of rodents • Predicted to protect immunogenic spermatids from immune responses and inflammation ?

  11. Pigtailed macaque model for HIV infection SIV infects the pigtailed macaque testis • Shehu-Xhilagaet al Retrovirology, 2007

  12. Aims • Are immune responses suppressed in the macaque testis? • How does SIV infection affect the testis? • Do testicular CD8 T cells respond to SIV infection?

  13. SIV infection of pigtailed macaques • Testes and blood taken from: • 7 uninfected macaques • 4 macaques infected with SIVmac239 • 10 weeks • 24 to 30 weeks

  14. Is there immunosuppression in the macaque testis? unstimulated mitogen stimulation

  15. Is there immunosuppression in the macaque testis? unstimulated mitogen stimulation Wilcoxon Signed Rank test • T cell responses in the testis are lower than in the blood

  16. Aims • Are immune responses suppressed in the macaque testis? • How does SIV infection affect the testis? • Do testicular CD8 T cells respond to SIV infection?

  17. SIV damages the macaques testis uninfected SIV week 10

  18. SIV alters testis leukocyte populations uninfected testis CD3+ SIV week 10 CD3+

  19. SIV alters testis leukocyte populations uninfected testis CD3+ SIV week 10 CD3+ blood blood testis testis

  20. SIV alters testis leukocyte populations uninfected testis CD3+ SIV week 10 CD3+ • SIV infection lead to: • Loss of CD4 T cells • Influx of CD8 T cells • Shift towards effector memory and away from central memory blood blood testis testis

  21. Aims • Are immune responses suppressed in the macaque testis? • How does SIV infection affect the testis? • Do testicular CD8 T cells respond to SIV infection?

  22. Are there CD8 T cell responses in the SIV-infected testis? uninfected testis CD8+ SIV week 10 CD8+ KP9-ManeA*084 tetramer KP9-ManeA*084 tetramer

  23. Are there CD8 T cell responses in the SIV-infected testis? uninfected testis CD8+ SIV week 10 CD8+ SIV-specific CD8 T cells in testis and blood blood testis KP9-ManeA*084 tetramer KP9-ManeA*084 tetramer • SIV-specific CD8 T cells were detected in the testis

  24. SIV inhibits CD8 T cell cytokine production SIV wk 10 testis CD8+ SIV wk 10 blood CD8+

  25. SIV inhibits CD8 T cell cytokine production SIV wk 10 testis CD8+ SIV wk 10 blood CD8+ Cytokine production after mitogen stimulation • SIV infection inhibited cytokine production by CD8 T cells in response to mitogens blood testis

  26. Summary • T cell responses to mitogens are relatively low in the macaque testis • Evidence for immune privilege in the primate testis • SIV infection affects the macaque testis: • Damage to the testis architecture • Influx of effector memory CD8 T cells • Loss of CD4 T cells

  27. Summary • SIV-specific CD8 T cells were detected in the testis • However cytokine production in response to mitogens was inhibited by SIV infection • Immunosuppression in the macaque testis reduces the ability of CD8 T cells to respond to infection, making the testis vulnerable to persistent SIV infection and damage. • Testicular immune privilege

  28. Acknowledgements Kent Lab, Doherty Institute University of Melbourne Stephen Kent Rob De Rose Sarah Lloyd Vinca Alcantara Thakshila Amarasena Marit Kramski Shayarana Gooneratne Hyon-Xhi Tan Monash University Mark Hedger Dept of Obstetrics and Gynaecology, University of Melbourne Jane Girling CSIRO AAHL Geelong Megan Schepers Lisa Reid

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