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

CD4

Ki67 CCR5

CD4

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

CD28 TN TM

CD95

CD28 TN TM

FYa1, euthanized DOL 10 FUa1, euthanized DOL 107

Oral mucosa