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Carol Vinton Laboratory of Dr. Jason Brenchley Laboratory of Molecular Microbiology

Differential SIV infection patterns of lymph node-resident CD4 T cells distinguishes progressive from non-progressive SIV infection. Carol Vinton Laboratory of Dr. Jason Brenchley Laboratory of Molecular Microbiology National Institute of Allergy and Infectious Diseases

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Carol Vinton Laboratory of Dr. Jason Brenchley Laboratory of Molecular Microbiology

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  1. Differential SIV infection patterns of lymph node-resident CD4 T cells distinguishes progressive from non-progressive SIV infection Carol Vinton Laboratory of Dr. Jason Brenchley Laboratory of Molecular Microbiology National Institute of Allergy and Infectious Diseases National Institutes of Health July 25th, 2012 AIDS 2012, HIV/SIV Pathogenesis Session

  2. SIVsmm SIVsyk SIVgsn SIVcol SIVagm SIVrcm SIVlho SIVmnd Sykes monkey Sooty mangabey SIVmac HIV-2 Greater spot-nosed monkey Mantled guereza SIV SIVcpz HIV-1 Chimpanzee African green monkey Red-capped mangabey Slide courtesy of Beatrice Hahn Mandrill L-Hoest’s monkey

  3. Natural Host (SM/AGM/etc) Non-Pathogenic Infection Non-Natural Host (RM/PTM/humans) Pathogenic Infection vs.

  4. Are there immunological mechanisms associated with non-progressive SIV infection in natural hosts? Nature Med. 2009 Aug;15(8):879-85. CD4 downregulation by memory CD4+ T cells in vivo renders African green monkeys resistant to progressive SIVagm infection. Beaumier CM, Harris LD, Goldstein S, Klatt NR, Whitted S, McGinty J, Apetrei C, Pandrea I,Hirsch VM, Brenchley JM. Lab of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, MD, USA. Nature Med. 2011 Jun 26;17(7):830-6. doi:10.1038/nm.2395. Low levels of SIV infection in sooty mangabey central memory CD4+ T cells are associated with limited CCR5 expression. Paiardini M,Cervasi B, Reyes-AvillesE, Micci L, Ortiz AM, Chahroudi A, Vinton C, Gordon SN, Bosinger SE, Francella N, Hallberg PL, Cramer E, Schlub T, Chan ML, Riddick NE, Collman RG, Apetrei C, Pandrea I, Else J, Munch J, Kirchhoff F, Davenport MP, Brenchley JM, Silvestri G. Yerkes National Primate Research Center, Emory Vaccine Center and Department of Pathology, Emory University, Atlanta, Georgia, USA. Mirko.paiardini@emory.edu 4+

  5. Experimental Layout Flow cytometrically sorted and analyzed CD4+ T cell subsets from PBMC and LN samples SM (natural, non-progressive SIV hosts) RM (non-natural, progressive SIV hosts) Analyzed SIV infection frequencies by qPCR

  6. CD4+ T cell subsets analyzed Naïve: mature, antigen inexperienced T cells, reside in blood and lymphoid tissue Effector Memory (EM): antigen experienced, reside in blood and effector tissues Central Memory (CM): antigen experienced, long-lived pool of precursors for additional memory and effector cells, reside in blood and lymphoid tissue T follicular helper (Tfh): antigen experienced, promote B cell proliferation and maturation, reside in lymphoid follicles

  7. Analysis and sorting of CD4+ T cell subsets Single Cells Lymphocytes Live cells CD3+ Live Lymphocytes Memory CD4+ cells Tfh cells CM CD4+ cells EM Naive CD4+ cells Tfh cells Non-Tfh cells

  8. SIV infected cell frequencies: PBMC SIVsmmE543-infected RM SIVmac239-infected RM SIVsmm-infected SM

  9. SIV infected cell frequencies: LN SIVsmmE543-infected RM SIVmac239-infected RM SIVsmm-infected SM

  10. Why are Tfh cells more prone to SIV infection in RM?

  11. Why are Tfh cells more prone to SIV infection in RM?

  12. SIV+ cells in the GC of lymph nodes Within follicles Extrafollicular T cell zone

  13. Trapping of Virions by FDCs

  14. Summary Different anatomical & cellular viral reservoirs in natural (SM) and non-natural (RM) hosts for SIV CM CD4+ T cells of RM are 2-10x more frequently infected than SM CM CD4+ T cells – both in PBMC and LN Frequency of SIV-infected CD4+ Tfh cells is higher in RMs compared to SMs LN SIV viral burden is greater in RM than SM Preferential infection of Tfh cells in RMs is possibly linked to increased viral trapping by FDCs Preferential infection of Tfh cells in RM may, in part, contribute to abnormal antibody responses observed during progressive SIV infection

  15. Acknowledgements Lab of Molecular Microbiology, NIAID, NIH Jason Brenchley Molly Perkins Lauren Canary Nichole Klatt AIDS and Cancer Virus Program, Frederick National Laboratory Jake Estes Jeff Lifson Brian Tabb Pathology and HistotechnologyLaboratory, Frederick National Laboratory Xing Pei Hao Lab of Molecular Microbiology, NAID, NIH Vanessa Hirsch NIH Animal Center Heather Cronise Joanna Swerczek Rick Herbert Division of Infectious Diseases, University of Colorado Denver Elizabeth Connick Emory University MirkoPairidini Guido Silvestri

  16. RM maintain similar overall frequencies of SIV infected naïve, EM, and CM CD4+ T cells as SIV-infected SM

  17. Maintenance of memory Tfh CD4+ T cell subset in SIV+ RM

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