ann chahroudi, md, phd division of pediatric infectious diseases and yerkes national primate...
TRANSCRIPT
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 MedicineAtlanta, GA, USA
Main features of SIV infection of natural vs. non-natural hosts
Chahroudi A et al, Science 2012
Low rates of mother-to-infant transmission in
natural hosts
THREE MECHANISTIC HYPOTHESES
• Low viral load in breast milk
• Innate inhibitory factors in milk
(work in progress)
• Highly active immune responses in infants
• Restricted availability of CD4+CCR5+ target cells
Chahroudi A et al, J Virol 2011
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
Infant sooty mangabeys have predominately naïve CD4+ T cells
Mean of values from 6 (GI tract) or 7 infants (lymphoid tissue)
Restricted expression of CCR5 on CD4+ T cells from infant mangabeys
CCR5 = main HIV/SIV coreceptor on target cells
Ki67 = marker of T cell proliferation
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
Spotlight on tissues related to breast milk transmission - 2
FYa1, euthanized DOL 10 FUa1, euthanized DOL 107
Oral mucosa
Esophagus
Tonsil
Ki67 CCR5
CD
4
Ki67 CCR5
CD
4
Infant macaques have ample SIV CD4+CCR5+ target cells
TN = CD28+CD95-CCR7+ TCM = CD28+CD95+CCR7+; TEM = CD28+/-CD95+CCR7-
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
Acknowledgements Silvestri Laboratory:
• Paul Carnathan• Diane Carnathan• Joana Yu• Katie Sheehan• Kathyrn Folkner• Emily Cartwright• Ron Trible• Tayebeh Hashempoor• Ankita Chowdhury• 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, Anapatricia Garcia• Barbara Cervasi• Mirko Paiardini• 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
Gated on CD3+CD4+ T lymphocytes
CD95
CD
28
TN TM
CD95
CD
28
TN TM
FYa1, euthanized DOL 10 FUa1, euthanized DOL 107
Oral mucosa