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Www.aids2014.org Comparison between Pathogenic and Nonpathogenic SIV Infections and Focus on Mucosal Tissue Compartment Reveal a Critical Role for the.

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Presentation on theme: "Www.aids2014.org Comparison between Pathogenic and Nonpathogenic SIV Infections and Focus on Mucosal Tissue Compartment Reveal a Critical Role for the."— Presentation transcript:

1 Comparison between Pathogenic and Nonpathogenic SIV Infections and Focus on Mucosal Tissue Compartment Reveal a Critical Role for the Adenosine Pathway in the Control of SIV-Related Immune Activation and Inflammation Tianyu He, Egidio Brocca-Cofano, Delbert G. Gillespie, Cuiling Xu, Jan Kristoff, Samantha Ross, Dongzhu Ma, George Haret-Richter, Charles R. Rinaldo, Cristian Apetrei, Edwin K. Jackson, Bernard J.C. Macatangay, Ivona Pandrea

2 Background Despite ART, mortality rate is still high in HIV-1 infected patients, due to end-organ diseases caused by persistent immune activation/inflammation. CD39/CD73/Adenosine pathway has been reported as one of the mechanisms used by Tregs to suppress immune activation/inflammation. CD26 + Its role in HIV/SIV infection?

3 NHP models of SIVagm infection AFRICAN GREEN MONKEY Natural host of SIVagm Maintenance of mucosal barrier Lack of microbial translocation Lack of chronic IA/INFL Lack of comorbidities Lack of disease progression PIGTAILED MACAQUE Non natural host of SIVagm Altered mucosal barrier Microbial translocation Chronic IA/INFL SIV comorbidities (CVD) Progression to AIDS

4 Experimental Strategy African green monkeys (AGMs): no progression to AIDS, no immune activation and inflammation (IA/INFL) Pigtail macaques (PTMs): progression to AIDS, substantial IA/INFL. Non-Progressive : AGMs (n=5) Non-Progressive : AGMs (n=5) Progressive: PTMs (n=5) Progressive: PTMs (n=5) Infect with SIVagm ADO/INO level in tissues was measured with mass spectrometry CD39/CD73 and CD26 expression is assessed by flow cytometry on T cells from blood, lymph nodes (LNs) and intestine (INT) Correlate with immune activation and proliferation markers

5 Mucosal Site Presents Substantial Coexpression of CD39 and CD73 on Tregs CD39 CD73 PBMC LN INT AGMs PTMs

6 Mucosal Site Presents Substantial Coexpression of CD39 and CD73 on Tregs  Almost no coexpression of CD39 and CD73 on Tregs in the blood, in both AGMs and PTMs.  Prior to infection, AGMs extensively coexpress CD39 and CD73 on Tregs in the intestine.  Such coexpression is not seen in PTMs prior to infection.

7 Mucosal Site Presents Substantial Coexpression of CD39 and CD73 on Tregs  After infection, the coexpression of CD39 and CD73 on Tregs increased significantly in PTMs in the INT.  Suggest possible increase in ADO production during progressive infection.

8 Adenosine Levels in the Tissues  ADO is intrinsically higher in AGMs in the INT and further increases in acute infection.  No significant change of ADO level was observed in lymph node.

9 CD26 Expression Increase Dramatically after Infection in PTMs in Intestine  In the intestine, CD26 expression increases dramatically after infection in PTMs.  In AGMs, CD26 expression remains around pre- infection level throughout the infection.

10 Inosine Levels in the Tissues  INO increased significantly at chronic infection stage in PTMs.  No significant change of INO level was observed in lymph node.

11 CD26 Expression on CD4 + T cells Correlates with Inosine Level  CD26 expression on CD4 + T cells correlates with INO level, and inversely correlates with ADO level in the gut.

12 ADO/INO Levels Correlates with Immune Activation/Proliferation Markers  Adenosine level in the gut inversely correlates with T cell proliferation.  Inosine level directly correlates with both CD4 + and CD8 + T cell proliferation and activation.

13 Exogenous ADO Suppress IFN-γ Production ADENOSINE CONTROL CD4 CD8 IFN-γ PBMCs CD3 CD28 stimulation + ADO - ADO cytokine production

14 Exogenous ADO Suppress Cytokine Production

15 Summary  Increased levels of ADO is sustained in the intestine of AGMs during SIVagm infection.  In PTMs, although CD39 and CD73 increased after infection, ADO production appears to be counteracted by a massive increase of CD26 which occurs very early after infection.  ADO plays a role in suppressing IA/INFL.  The adenosine pathway is significantly involved in the control of IA/INFL in the nonprogressive non-human primate model.  Changes of ADO-associated markers predominately occur in the gut, suggesting that future study about this pathway in the context of HIV/SIV infection should focus on the mucosal site.

16 Acknowledgement Pandrea/Apetrei lab Egidio Brocca-Cofano Jan Kristoff George Haret-Richter Ross Samantha Cuiling Xu Jennifer Stock Cristian Apetrei Ivona Pandrea Edwin Jackson lab Delbert G. Gillespie Edwin K. Jackson Bernard J.C. Macatangay MD Charles R. Rinaldo, Jr. PhD


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