CD4+ memory stem cells (T SCM ) in pathogenic and non- pathogenic SIV infections Guido Silvestri, MD...
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Transcript of CD4+ memory stem cells (T SCM ) in pathogenic and non- pathogenic SIV infections Guido Silvestri, MD...
![Page 1: CD4+ memory stem cells (T SCM ) in pathogenic and non- pathogenic SIV infections Guido Silvestri, MD Yerkes National Primate Research Center Emory University.](https://reader035.fdocuments.us/reader035/viewer/2022062421/56649e3f5503460f94b2f502/html5/thumbnails/1.jpg)
CD4+ memory stem cells (TSCM) in pathogenic and non-
pathogenic SIV infections
Guido Silvestri, MDYerkes National Primate Research Center
Emory University School of Medicine
Emory Center for AIDS Research (CFAR)
Emory Vaccine Center
![Page 2: CD4+ memory stem cells (T SCM ) in pathogenic and non- pathogenic SIV infections Guido Silvestri, MD Yerkes National Primate Research Center Emory University.](https://reader035.fdocuments.us/reader035/viewer/2022062421/56649e3f5503460f94b2f502/html5/thumbnails/2.jpg)
The pattern of Infected CD4+ T Cell is a key determinant of AIDS pathogenesis
Damage to LN architecture &lymphoid niche
Loss of CD4 T cellhomeostasis/CD4 depletion
Chronic immune activation
Pattern of in vivoinfected cells
Features & efficacy of host immuneresponses
Size and dynamics of the “latent” reservoir
Picker . J Exp Med 2007; Letvin et al. Science 2007; Roederer et al. J Exp Med 2007; Brenchley et al. Immunity 2010; Chomont et al., Nat Med 2009; Paiardini et al. Nat Med 2011; Brenchley et al. Blood 2012; Autran et al., Clin Inf Dis 2012; Chahroudi et al., Science 2012; Saez-Cirion et al. PLoS Path 2013
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Comparative AIDS Research
AIDS NO YES YES
Blood CD4 depletion Rare YES YES
Viral Load HIGH HIGH HIGH
SM RM HIV
Preserved gut & LN integrity YES NO NO
Microbial translocation NO YES YES
Chronic immune activation NO YES YES
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Restricted infection of CD4+ TCM cells in SIV-infected sooty mangabeys
Level of infected cells
in vivo
Level of infected cells following in
vitro infection
Paiardini et al, Nat Med 2011
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LN anatomic distribution of productively infected cells in RMs, humans, and SMs. (A) SIV/HIV vRNA+ cells/mm2 in LNs of chronically infected RMs, humans, and SMs. (B) SIV/HIV vRNA+ in B-cell follicles (C) Percentage of LN area that consists of B-cell follicles.
Brenchley et al, Blood 2012
Higher levels of Tfh infection in SIV-infected RMs and HIV-infected humans than SIV-infected SMs
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Progressive Infection and AIDS
Chronic, generalized Immune Activation
How HIV and SIV infection cause AIDS:Lessons from natural SIV infections
Virus replication in central memory
CD4+ T cells
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Naïve Cell Effector (short-lived, activated)
Memory cell pool
Proliferation and clonal expansion in response to antigenic stimulation
Contraction phase
Effector Memory: Resident in periphery. Able to respond quickly to re-exposure.CD62L- CCR7-
Central Memory: Resident in LNs, spleen. Able to self-renew and differentiate into Tem.CD62L+ CCR7+
Memory stem cell
antigen
Complexity of the memory CD4+ T cell pool
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What is a T memory stem cell (Tscm)?
• 1-3% of circulating and LN-based CD4+ and CD8+ T cells.
• Identified by classical naïve T cell markers (CD45R+CD45RO-CD62L+CCR7+CD127+CD27+CD28+), but also CD95 & CD122.
• Express more LFA-1 and CXCR3 than naïve cells, but less than TCM (and less Bcl-2 than naïve cells but more than TCM).
• Least differentiated memory subset, with high proliferative potential, and capable of self-renewal.
• Multipotent: able to generate both TCM and TEM
Gattinoni et al., Nat Med 2009; Turtle et al., Immunity 2009; Muranski et al., Immunity 2011; Gattinoni et al., Nat Med 2011; Luckey CJ, Weaver CT. Cell Stem Cell, 2012; Roederer et al., J Clin Invest, 2012
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A.
TSCM
CD
8F
SC
-HC
D95
SS
C-A
CC
R7
Dea
d/1
4/16
/20
CD
27
CD45RA CD28CD4
CD122
FSC-A CD3FSC-A
Identification of CD4+TSCM in healthy rhesus macaques and sooty mangabeys.
E.
C.
B.
D.
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A.
E.
C.
B.
D.
F.
Identification of CD4+TSCM in healthy rhesus macaques and sooty mangabeys.
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B.
C.
CD4+ TSCM express levels of CXCR3 and CD11a similar to other memory CD4+ T cells subsets, and levels of Bcl-2 that are intermediate between naïve and TCM.
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A.
Higher levels of CCR5 expression on CD4+TSCM of healthy RMs as compared to SMs.
C.
B.
D.
E.
F.
CD
4
SM
RM
CCR5
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Selective preservation of CD4+TSCM cells during pathogenic SIV infection of RMs
B. D.
A.
p= n.s. p= n.s.
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SIV infection of RMs is associated with a significant depletion of CCR5+CD4+TSCM.
A.
B.
C.
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SIV infection of RMs is associated with increased proliferation of CD4+TSCM that significantly inversely correlates with the levels of CD4+TCM
A. B.
C.
D.
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A.
B.
C.
Dynamics of CD4+TSCM during non-pathogenic infection of SM
D.
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Robust levels of CD4+TSCM infection in vivo are observed in SIV-infected RMs but not in SIV-infected SMs
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CD4+ T memory stem cells in pathogenic and non-pathogenic SIV infections
• CD4+ TSCM are numerically preserved during BOTH pathogenic and nonpathogenic SIV infections.
• However, SIV-infected RM show (i) a selective depletion of CD4+CCR5+ TSCM; and (ii) higher levels of CD4+ TSCM proliferation that correlate significantly with the level of CD4+ TCM depletion.
• Robust levels of direct virus infection of CD4+ TSCM are found only in SIV-infected RM, with 6 out of 7 SIV-infected SM showing no evidence of CD4+ TSCM infection.
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CD4+ T memory stem cells in pathogenic and non-pathogenic SIV infections
RM
SMTSCM TCM
CCR5+ Ki67+
TSCM TCMSIV
AIDS
TSCM TCM
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Increasing contribution of Tscm to HIV reservoir over time (M. Lichterfeld)
Lichterfeld, unpublished
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Hypothesis: can reservoirs be eliminated when there is no virus in TSCM cells?
TSCM TCM TEM
ART
TSCM TCM TEM
Persistent TSCM (and TCM) reservoirs
Absence of TSCM (and TCM) reservoirs
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Acknowledgments
Silvestri LabEmily CartwrightVandy Vanderford Steven BosingerAnn ChahroudiAnkita ChowdhuryMaud MavignerKiran MirTim HayesLuca MicciTayebeh HashempourCharlene WangAlex Ortiz (NIH)Nichole Klatt (UW)Diane Carnathan Paul Carnathan
SBRI -- SeattleDonald Sodora
Emory University/YerkesMirko PaiardiniColleen McGaryCynthia DerdeynJames ElseEric HunterVincent MarconiRay Schinazi
NIH/NIAID/NCIJake EstesJason BrenchleyDaniel Douek
Univ. of Pennsylvania Ron CollmanMike BettsBeatrice Hahn
Univ. of UlmFrank Kirchhoff
Ragon Institute/HMSMathias Lichterfeld
Case WesternMichael Lederman
Institut PasteurMichaela Muller-Trutwin
University of PittsburghIvona Pandrea Cristian Apetrei
Los Alamos National LabsAlan Perelson
Supported by NIH/NIAID, Emory CFAR, Georgia Research Alliance