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

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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?