2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune...
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Transcript of 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune...
![Page 1: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/1.jpg)
2014 “Towards an HIV Cure” symposiumMelbourne
SIV infection of the macaque testis – an immune privileged site
Wendy Winnall, University of Melbourne
![Page 2: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/2.jpg)
?
HIV persistence in the testis?
Does HIV persist in the testis?
Why should we care?
•Transmission through seminal plasma?
•Reservoir during cART?
![Page 3: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/3.jpg)
Is the testis a sanctuary for HIV?
Possible mechanisms for HIV persistence in the testis:
•Blood testis barrier?
•Testicular immune privilege? ?
![Page 4: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/4.jpg)
Cells of the testis
Lumen
blood vessel
Seminiferous tubuleInterstitium
lymphatic vessel
![Page 5: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/5.jpg)
Cells of the testis
Lumen
blood vessel
Seminiferous tubuleInterstitium
lymphatic vessel
Spermatocytes
Spermatogonia
Spermatids
![Page 6: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/6.jpg)
Cells of the testis
Lumen
blood vessel
Seminiferous tubuleInterstitium
lymphatic vessel
Sertoli cells
![Page 7: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/7.jpg)
Cells of the testis
Lumen
blood vessel
Seminiferous tubuleInterstitium
lymphatic vessel
Sertoli cells
Blood-testis barrier
Pgp
![Page 8: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/8.jpg)
Cells of the testis
Lumen
blood vessel
Seminiferous tubuleInterstitium
lymphatic vessel Leydig cells
Sertoli cells
Leukocytes:macrophagesT cells
Blood-testis barrier
Pgp
![Page 9: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/9.jpg)
Is the testis a sanctuary for HIV?
Possible mechanisms for HIV persistence in the testis:
•Blood testis barrier?
•Testicular immune privilege? ?
![Page 10: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/10.jpg)
?
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
![Page 11: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/11.jpg)
Pigtailed macaque model for HIV infection
SIV infects the pigtailed macaque testis
Shehu-Xhilaga et al Retrovirology, 2007
![Page 12: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/12.jpg)
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?
![Page 13: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/13.jpg)
SIV infection of pigtailed macaques
Testes and blood taken from:
•7 uninfected macaques
•4 macaques infected with SIVmac239
• 10 weeks
• 24 to 30 weeks
![Page 14: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/14.jpg)
Is there immunosuppression in the macaque testis?
unstimulated mitogen stimulation
![Page 15: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/15.jpg)
Is there immunosuppression in the macaque testis?
unstimulated mitogen stimulation
• T cell responses in the testis are lower than in the blood
Wilcoxon Signed Rank test
![Page 16: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/16.jpg)
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?
![Page 17: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/17.jpg)
SIV damages the macaques testis
uninfected SIV week 10
![Page 18: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/18.jpg)
SIV alters testis leukocyte populations
uninfected testis CD3+ SIV week 10 CD3+
![Page 19: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/19.jpg)
SIV alters testis leukocyte populations
uninfected testis CD3+ SIV week 10 CD3+
blood
testis
blood
testis
![Page 20: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/20.jpg)
SIV alters testis leukocyte populations
uninfected testis CD3+ SIV week 10 CD3+
blood
testis
blood
testis
SIV infection lead to:
•Loss of CD4 T cells
•Influx of CD8 T cells
• Shift towards effector memory and away from central memory
![Page 21: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/21.jpg)
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?
![Page 22: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/22.jpg)
Are there CD8 T cell responses in the SIV-infected testis?
uninfected testis CD8+ SIV week 10 CD8+
KP
9-M
aneA
*084
tet
ram
er
KP
9-M
aneA
*084
tet
ram
er
![Page 23: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/23.jpg)
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
KP
9-M
aneA
*084
tet
ram
er
KP
9-M
aneA
*084
tet
ram
er
• SIV-specific CD8 T cells were detected in the testis
blood
testis
![Page 24: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/24.jpg)
SIV inhibits CD8 T cell cytokine production
SIV wk 10 testis CD8+ SIV wk 10 blood CD8+
![Page 25: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/25.jpg)
SIV inhibits CD8 T cell cytokine production
blood
testis
• SIV infection inhibited cytokine production by CD8 T cells in response to mitogens
SIV wk 10 testis CD8+ SIV wk 10 blood CD8+ Cytokine production after mitogen stimulation
![Page 26: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/26.jpg)
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
![Page 27: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/27.jpg)
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
![Page 28: 2014 “Towards an HIV Cure” symposium Melbourne SIV infection of the macaque testis – an immune privileged site Wendy Winnall, University of Melbourne.](https://reader035.fdocuments.in/reader035/viewer/2022062804/56649cec5503460f949b813f/html5/thumbnails/28.jpg)
Acknowledgements
Kent Lab, Doherty InstituteUniversity of MelbourneStephen KentRob De RoseSarah LloydVinca AlcantaraThakshila AmarasenaMarit KramskiShayarana GooneratneHyon-Xhi Tan
Monash UniversityMark Hedger
Dept of Obstetrics and Gynaecology, University of MelbourneJane Girling
CSIRO AAHL GeelongMegan SchepersLisa Reid