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? ?

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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

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tet

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KP

9-M

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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

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tet

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KP

9-M

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• 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