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Target cell availability dictates mother-to-infant transmission of SIV

Target cell availability dictates mother-to-infant transmission of SIV. Ann Chahroudi, MD, PhD Division of Pediatric Infectious Diseases and Yerkes National Primate Research Center, Emory University School of Medicine Atlanta, GA, USA.

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Target cell availability dictates mother-to-infant transmission of SIV

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  1. Target cell availability dictates mother-to-infant transmission of SIV Ann Chahroudi, MD, PhD Division of Pediatric Infectious Diseases and Yerkes National Primate Research Center, Emory University School of Medicine Atlanta, GA, USA

  2. Main features of SIV infection of natural vs. non-natural hosts Chahroudi A et al, Science 2012

  3. Low rates of mother-to-infant transmission in natural hosts THREE MECHANISTIC HYPOTHESES • Highly active immune responses in infants • Low viral load in breast milk • Innate inhibitory factors in milk • (work in progress) • Restricted availability of CD4+CCR5+ target cells Chahroudi A et al, J Virol2011

  4. Experimental methods Multicolor flow cytometry to measure SIV target cells in bulk, naïve, and memory CD4+ T cells from infant sooty mangabey tissues at necropsy Direct comparison of the levels of SIV target cells found in the peripheral blood of infant sooty mangabeys and rhesus macaques

  5. Infant sooty mangabeys have predominately naïve CD4+ T cells Mean of values from 6 (GI tract) or 7 infants (lymphoid tissue)

  6. Restricted expression of CCR5 on CD4+ T cells from infant mangabeys Ki67 = marker of T cell proliferation CCR5 = main HIV/SIV coreceptor on target cells

  7. Spotlight on tissues related to breast milk transmission - 1 Milush JM, et al AIDS 2004 Oral inoculation of neonatal rhesus macaques with SIV • Anatomical distribution of SIV DNA early after infection: • Oral mucosa • Tonsils • Esophagus • Lymphoid tissue

  8. Spotlight on tissues related to breast milk transmission - 2 FYa1, euthanized DOL 10 FUa1, euthanized DOL 107 Oral mucosa Esophagus Tonsil CD4 CD4 Ki67 CCR5 Ki67 CCR5

  9. Infant macaques have ample SIV CD4+CCR5+ target cells TN = CD28+CD95-CCR7+ TCM = CD28+CD95+CCR7+; TEM = CD28+/-CD95+CCR7-

  10. Summary Mother-to-infant transmission of SIV is rare in natural hosts Robust proliferation of both naïve and memory T cells is present in infant sooty mangabeys Infant sooty mangabeys, unlike rhesus macaques, are characterized by limited availability of CD4+CCR5+ target cells for SIV Target cell restriction likely represents a key evolutionary adaptation to reduce the risk of mother-to-infant transmission in natural hosts

  11. Acknowledgements • Silvestri Laboratory: • Paul Carnathan • Diane Carnathan • Joana Yu • Katie Sheehan • KathyrnFolkner • Emily Cartwright • Ron Trible • TayebehHashempoor • AnkitaChowdhury • Charlene Wang • Alexandra Ortiz • Tim Hayes • Kiran Mir • Steve Bosinger • Thomas Vanderford • Emory: • Paul Spearman • Eric Hunter • Larry Anderson • YNPRC: • Benton Lawson • Tracy Meeker • Stephanie Ehnert • Joyce Cohen, Maria Crane • Cindy Courtney, Prachi Sharma, AnapatriciaGarcia • Barbara Cervasi • MirkoPaiardini • Francois Villinger • Jim Else • Duke: • Sallie Permar • Funding Sources: • Emory CFAR03 Developmental Award • NIH R37 AI66998 to G. Silvestri • NIH P51 DO-00165 to YNPRC

  12. CD28 TN TM FYa1, euthanized DOL 10 FUa1, euthanized DOL 107 CD28 TN TM CD95 Oral mucosa CD95 Gated on CD3+CD4+ T lymphocytes

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