2014 “Towards an HIV Cure” symposium Melbourne
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Transcript of 2014 “Towards an HIV Cure” symposium Melbourne
2014 “Towards an HIV Cure” symposiumMelbourne
SIV infection of the macaque testis – an immune privileged site
Wendy Winnall, University of Melbourne
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HIV persistence in the testis?
Does HIV persist in the testis?
Why should we care?
•Transmission through seminal plasma?
•Reservoir during cART?
Is the testis a sanctuary for HIV?
Possible mechanisms for HIV persistence in the testis:
•Blood testis barrier?
•Testicular immune privilege? ?
Cells of the testis
Lumen
blood vessel
Seminiferous tubuleInterstitium
lymphatic vessel
Cells of the testis
Lumen
blood vessel
Seminiferous tubuleInterstitium
lymphatic vessel
Spermatocytes
Spermatogonia
Spermatids
Cells of the testis
Lumen
blood vessel
Seminiferous tubuleInterstitium
lymphatic vessel
Sertoli cells
Cells of the testis
Lumen
blood vessel
Seminiferous tubuleInterstitium
lymphatic vessel
Sertoli cells
Blood-testis barrier
Pgp
Cells of the testis
Lumen
blood vessel
Seminiferous tubuleInterstitium
lymphatic vessel Leydig cells
Sertoli cells
Leukocytes:macrophagesT cells
Blood-testis barrier
Pgp
Is the testis a sanctuary for HIV?
Possible mechanisms for HIV persistence in the testis:
•Blood testis barrier?
•Testicular immune privilege? ?
?
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
Pigtailed macaque model for HIV infection
SIV infects the pigtailed macaque testis
Shehu-Xhilaga et al Retrovirology, 2007
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?
SIV infection of pigtailed macaques
Testes and blood taken from:
•7 uninfected macaques
•4 macaques infected with SIVmac239
• 10 weeks
• 24 to 30 weeks
Is there immunosuppression in the macaque testis?
unstimulated mitogen stimulation
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
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?
SIV damages the macaques testis
uninfected SIV week 10
SIV alters testis leukocyte populations
uninfected testis CD3+ SIV week 10 CD3+
SIV alters testis leukocyte populations
uninfected testis CD3+ SIV week 10 CD3+
blood
testis
blood
testis
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
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?
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
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
SIV inhibits CD8 T cell cytokine production
SIV wk 10 testis CD8+ SIV wk 10 blood CD8+
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
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
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
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