Transcript CD4+ memory stem cells (TSCM) in pathogenic and nonpathogenic SIV infections Guido Silvestri, MD Yerkes National Primate Research Center Emory University School of Medicine Emory.

CD4+ memory stem cells (TSCM)
in pathogenic and nonpathogenic SIV infections
Guido Silvestri, MD
Yerkes National Primate Research Center
Emory University School of Medicine
Emory Center for AIDS Research (CFAR)
Emory Vaccine Center
The pattern of Infected CD4+ T Cell is a key
determinant of AIDS pathogenesis
Loss of CD4 T cell
homeostasis/CD4 depletion
Features & efficacy
of host immune
responses
Pattern of in vivo
infected cells
Chronic immune activation
Damage to LN
architecture &
lymphoid niche
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
Comparative AIDS Research
SM
RM
HIV
AIDS
NO
YES
YES
Blood CD4 depletion
Rare
YES
YES
Viral Load
HIGH
HIGH
HIGH
Preserved gut & LN integrity
YES
NO
NO
Microbial translocation
NO
YES
YES
Chronic immune activation
NO
YES
YES
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
Higher levels of Tfh infection in SIV-infected RMs
and HIV-infected humans than SIV-infected SMs
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
How HIV and SIV infection cause AIDS:
Lessons from natural SIV infections
Chronic, generalized
Immune Activation
Virus replication
in central memory
CD4+ T cells
Progressive Infection and AIDS
Complexity of the memory CD4+ T cell pool
antigen
Naïve Cell
Proliferation and clonal
expansion in response
to antigenic stimulation
Effector
(short-lived, activated)
Contraction phase
Memory cell pool
Memory
stem cell
Central Memory:
Effector Memory:
Resident in LNs, spleen.
Able to self-renew and
differentiate into Tem.
CD62L+ CCR7+
Resident in periphery.
Able to respond quickly to
re-exposure.
CD62L- CCR7-
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+CD45ROCD62L+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
CD8
B
.
CD4
CD45RA
CD95
TSCM
CD122
E
.
CD3
CD27
FSC-A
CCR7
FSC-A
D.
Dead/14/16/20
FSC-H
A
.
SSC-A
Identification of CD4+TC.SCM in healthy rhesus
macaques and sooty mangabeys.
CD28
Identification of CD4+TC.SCM in healthy rhesus
macaques and sooty mangabeys.
A
.
D.
E
.
B
.
F.
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.
B.
C.
C.
Higher levels of CCR5 expression
on CD4+TSCM
of healthy RMs as compared to SMs.
A
.
D.
5.1
CD4
B
.
E
.
13.7
1.7
RM
F
.
SM
CCR5
Selective preservation of CD4+TSCM cells during
A. pathogenic SIV infection of RMs
B.
D.
p= n.s.
p= n.s.
A.
SIV infection of RMs is associated with a
significant depletion of CCR5+CD4+TSCM.
B
.
C.
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.
A.
Dynamics of CD4+T
SCM during non-pathogenic
infection of SM
B.
C.
D.
Robust levels of CD4+TSCM infection in vivo are observed
in SIV-infected RMs but not in SIV-infected SMs
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.
CD4+ T memory stem cells in pathogenic
and non-pathogenic SIV infections
CCR5+
TSCM
Ki67+
TCM
RM
AIDS
SM
TSCM
TCM
SIV
TSCM
TCM
Increasing contribution of Tscm to HIV
reservoir over time (M. Lichterfeld)
Lichterfeld, unpublished
Hypothesis: can reservoirs be eliminated
when there is no virus in TSCM cells?
ART
TSCM
TCM
TEM
TSCM
TCM
TEM
Persistent TSCM (and TCM) reservoirs
Absence of TSCM (and TCM) reservoirs
Acknowledgments
Silvestri Lab
Emily Cartwright
Vandy Vanderford
Steven Bosinger
Ann Chahroudi
Ankita Chowdhury
Maud Mavigner
Kiran Mir
Tim Hayes
Luca Micci
Tayebeh Hashempour
Charlene Wang
Alex Ortiz (NIH)
Nichole Klatt (UW)
Diane Carnathan
Paul Carnathan
Emory University/Yerkes
Mirko Paiardini
Colleen McGary
Cynthia Derdeyn
James Else
Eric Hunter
Vincent Marconi
Ray Schinazi
Ragon Institute/HMS
Mathias Lichterfeld
NIH/NIAID/NCI
Jake Estes
Jason Brenchley
Daniel Douek
University of Pittsburgh
Ivona Pandrea
Cristian Apetrei
SBRI -- Seattle
Donald Sodora
Univ. of Ulm
Frank Kirchhoff
Univ. of Pennsylvania
Ron Collman
Mike Betts
Beatrice Hahn
Case Western
Michael Lederman
Institut Pasteur
Michaela Muller-Trutwin
Los Alamos National Labs
Alan Perelson
Supported by NIH/NIAID,
Emory CFAR, Georgia
Research Alliance