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Mirko Paiardini , PhD Emory University, YNPRC

Low levels of SIV infection in SM CD4 + T CM cells are associated with limited CCR5 expression. Mirko Paiardini , PhD Emory University, YNPRC. IAS 2011, Rome, July 20 th , 2011. Comparative AIDS Research.

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Mirko Paiardini , PhD Emory University, YNPRC

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  1. Low levels of SIV infection in SM CD4+ TCM cells are associated with limited CCR5 expression MirkoPaiardini, PhD Emory University, YNPRC IAS 2011, Rome, July 20th, 2011

  2. Comparative AIDS Research • 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 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

  3. CD4+ T cell depletion is not sufficient to induce AIDS in SM AGM SM Humans RM Mir K et al, Microbes Infect 2011 Brenchley & Paiardini, Blood 2011

  4. differentiation status CD4+ T cells are very heterogeneous effector functions Th1 Th2 R. Ahmed et al, Nature Rev Immunol 2002 Th17 Novel working model of HIV pathogenesis: The quality of preserved CD4+ T cells is more important than the quantity

  5. Infection and depletion of TCM cells is crucial for progression to AIDS AIDS RMs 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” Letvinet al. Preserved CD4 TCM cells and survival in vaccinated SIV-challenged monkeys. Science 2006; Mattapallilet al. Vaccination preserves CD4 TCM cells during acute SIV challenge. J Exp Med 2006

  6. 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

  7. SM CD4+ TCM are relatively resistant to SIV infection • 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. Paiardini et al, Nat Med 2011

  8. SM CD4+ TCM are relatively resistant to SIV infection • level of in vitro infection determined in SORTED CD4+ TCM and TEM • CD4+ TCM and TEMactivated (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. Paiardini et al, Nat Med 2011

  9. 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

  10. Multiple ways to protect CD4+ TCM in SIV-infected natural host Rare animals with X4-tropic viruses are protected by expanding CD4-negative TCM helper cells ~5-7% of animals protected by knocking down CCR5 gene on ALL cells Protected by down-modulating CD4 expression during naïve to memory CD4+ T cell transition >90% of animals protected by down-modulating CCR5 on CD4+ TCM 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 AGMs Sooty mangabeys

  11. Protection of CD4+ TCM is a key determinant of the benign nature of SIV infection in SM Maintenance of CD4 T cell homeostasis Resolution of immune activation & residual inflammation Maintenance of LN architecture & lymphoid niche Low virus replication in CD4+ TCM cells Non-Progressive Infection

  12. Acknowledgments University of Pennsylvania Ron Collman NadeeneRiddick Nicholas Francella Paul Hallberg Hank Pletcher National Institutes of Health Jason Brenchley Carol Vinton Daniel Douek Jeff Lifson Jake Estes Case Western Michael Lederman and the CLIC/BBC Paiardini Lab Barbara Cervasi Luca Micci Zachary Ende Michelle Bonkosky University of Pittsburgh IvonaPandrea CristianApetrei Emory University Bob Mittler Francois Villinger Tab Ansari Yerkes Primate Center Elizabeth Strobert Stephanie Ehnert Tracy Meeker James Else Silvestri Lab Ann Chahroudi Paul Carnathan Diane Carnathan Alex Ortiz VandyVanderford Steven Bosinger Kiran Mir Tim Hayes Katherine Sheehan Kathryn Folkner Univ. of Ulm Frank Kirchhoff Jan Munch Supported by NIH (R01, R56)

  13. Implications for HIV infection in humans Is the infection of CD4+ TCM a prognostic marker of both HIV-associated immune activation and disease progression? Is residual infection of CD4+ TCM in ART-treated individuals a predictor of persistent immune activation and poor immune reconstitution? Could therapy aimed at preventing or reducing virus infection of CD4+ TCM have a beneficial impact on the course of HIV disease?

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