Post on 13-Jan-2016
Low levels of SIV infection in SM CD4+ TCM cells are associated with limited CCR5 expression
Mirko Paiardini, PhD
Emory University, YNPRC
IAS 2011, Rome, July 20th, 2011
Comparative AIDS Research
Understanding why natural SIV infections are nonprogressive
is a key priority in contemporary AIDS research, with important
implications in terms of HIV pathogenesis, therapy and vaccines
HIV-1 infection of humans and SIV infection of Asian macaques leads, if left untreated, to AIDS
SIV infections of African monkey species that are infected in the wild are typically non pathogenic
Sooty mangabey Vervet monkey Mandrill
Mir K et al, Microbes Infect 2011Brenchley & Paiardini, Blood 2011
CD4+ T cell depletion is not sufficient to induce AIDS in SM
AGM SM Humans RM
differentiation status
R. Ahmed et al, Nature Rev Immunol 2002
Th1
Th2
Th17
effector functions
CD4+ T cells are very heterogeneous
Novel working model of HIV pathogenesis: The quality of preserved CD4+ T cells is more important than the quantity
RMs
Infection and depletion of TCM cells is crucial for progression to AIDS
AIDS
Picker et al. Progressive CD4 TCM decline results in CD4 TEM insufficiency and overt disease in
chronic SIV infection. J Exp Med 2007;
“the tempo of disease onset is largely determined by destruction and gradual decline of CD4 TCM”
Letvin et al. Preserved CD4 TCM cells and survival in vaccinated SIV-challenged monkeys. Science 2006;
Mattapallil et al. Vaccination preserves CD4 TCM cells during acute SIV challenge. J Exp Med 2006
SM CD4+ TCM are relatively resistant to SIV infection
CD4+ TCM and TEM cells purified from 18 SIV-infected SM and 7 SIV-infected RM
in vivo frequency of infection determined by quantification of copy numbers of cell-associated SIVgag-DNA by q-PCR
Paiardini et al, Nat Med 2011
in vitro frequency of infection determined by using a molecular clone of SIVsmm expressing GFP.
PBMCs activated with ConA + IL-2, infected at day 3, GFP staining is measured at day 7.
SM CD4+ TCM are relatively resistant to SIV infection
Paiardini et al, Nat Med 2011
level of in vitro infection determined in SORTED CD4+ TCM and TEM
CD4+ TCM and TEM activated (ConA + IL-2), infected at day 3, and p27 levels in the supernatants were measured at day 3, 6, 9, 12, and 15 post-infection.
SM CD4+ TCM are relatively resistant to SIV infection
Paiardini et al, Nat Med 2011
Low fraction of CCR5+ cells after in vitro activation of SM CD4+ TCM
CD4+ TCM of SM and RM are similarly recruited to cell cycle
Paiardini et al, Nat Med 2011
Multiple ways to protect CD4+ TCM in SIV-infected natural host
Sooty mangabeys
>90%
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als
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ating
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n CD
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ene
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ith X
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opic
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ses
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4 ex
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rans
ition
Paiardini et al.Nat Med 2011
Reddick et al.PLoS Pathogens 2010
Milush, Mir et al.J Clin Invest 2011
Beaumier et al.Nat Med 2009
Low virus replication in
CD4+ TCM cells
Maintenance of CD4 T cellhomeostasis
Resolution of immune activation & residual inflammation
Maintenance of LN architecture &lymphoid niche
Non-Progressive Infection
Protection of CD4+ TCM is a key determinant of the benign nature of SIV infection in SM
Acknowledgments
Paiardini LabBarbara CervasiLuca MicciZachary EndeMichelle Bonkosky
University of PittsburghIvona Pandrea Cristian Apetrei
Emory UniversityBob MittlerFrancois VillingerTab Ansari
Yerkes Primate Center Elizabeth StrobertStephanie EhnertTracy MeekerJames Else
University of PennsylvaniaRon CollmanNadeene RiddickNicholas FrancellaPaul HallbergHank Pletcher
National Institutes of HealthJason BrenchleyCarol VintonDaniel DouekJeff LifsonJake Estes
Case WesternMichael Lederman and the CLIC/BBC
Supported by NIH (R01, R56)
Silvestri LabAnn ChahroudiPaul CarnathanDiane Carnathan Alex OrtizVandy Vanderford Steven BosingerKiran MirTim HayesKatherine SheehanKathryn Folkner
Univ. of UlmFrank KirchhoffJan Munch
Implications for HIV infection in humans
1. Is the infection of CD4+ TCM a prognostic marker of both HIV-associated immune activation and disease progression?
2. Is residual infection of CD4+ TCM in ART-treated individuals a predictor of persistent immune activation and poor immune reconstitution?
3. Could therapy aimed at preventing or reducing virus infection of CD4+ TCM have a beneficial impact on the course of HIV disease?