C A R O L V I N T O N

L A B O R A T O R Y O F D R . J A S O N B R E N C H L E YL A B O R A T O R Y O F M O L E C U L A R M I C R O B I O L O G Y

N A T I O N A L I N S T I T U T E O F A L L E R G Y A N D I N F E C T I O U S D I S E A S E S

N A T I O N A L I N S T I T U T E S O F H E A LT H

J U L Y 2 5 T H , 2 0 1 2A I D S 2 0 1 2 , H I V / S I V PA T H O G E N E S I S S E S S I O N

Differential SIV infection patterns of lymph node-resident CD4 T cells distinguishes progressive from non-

progressive SIV infection

Sooty mangabey

SIVcpz

Chimpanzee

HIV-1

SIV

SIVsyk

Sykes monkey

SIVcol

Mantled guereza

L-Hoest’s monkey Mandrill

SIVlho

SIVrcm

SIVgsn

SIVmnd

Red-capped mangabey

SIVagm

African green monkey

SIVsmm

Greater spot-nosed monkey

Slide courtesy of Beatrice Hahn

HIV-2

SIVmac

Natural Host (SM/AGM/etc)

Non-Pathogenic Infection

Non-Natural Host (RM/PTM/humans)

Pathogenic Infection

Yes High Viral Load Yes

Rare Depletion of Peripheral CD4+ Yes

Some Acute Depletion of Mucosal CD4+ Yes

No Progressive Depletion of Mucosal CD4+ Yes

No Preferential depletion of Th17 Yes

No Microbial Translocation Yes

No Immune Activation Yes

No Progression to AIDS Yes

vs.

Nature Med. 2011 Jun 26;17(7):830-6. doi:10.1038/nm.2395.Low levels of SIV infection in sooty mangabey central memory CD4+ T cells are associated with limited CCR5 expression.Paiardini M, Cervasi B, Reyes-Avilles E, Micci L, Ortiz AM, Chahroudi A, Vinton C, Gordon SN, Bosinger SE, Francella N, Hallberg PL, Cramer E, Schlub T, Chan ML, Riddick NE, Collman RG, Apetrei C, Pandrea I, Else J, Munch J, Kirchhoff F, Davenport MP, Brenchley JM, Silvestri G.Yerkes National Primate Research Center, Emory Vaccine Center and Department of Pathology, Emory University, Atlanta, Georgia, USA. Mirko.paiardini@emory.edu

Are there immunological mechanisms associated with non-

progressive SIV infection in natural hosts?

4+

Nature Med. 2009 Aug;15(8):879-85.CD4 downregulation by memory CD4+ T cells in vivo renders African green monkeys resistant to progressive SIVagm infection.Beaumier CM, Harris LD, Goldstein S, Klatt NR, Whitted S, McGinty J, Apetrei C, Pandrea I, Hirsch VM, Brenchley JM.Lab of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, MD, USA.

Experimental Layout

Flow cytometrically sorted and analyzed CD4+ T cell subsets from PBMC and LN samples

SM (natural, non-progressive SIV hosts)RM (non-natural, progressive SIV hosts)Analyzed SIV infection frequencies by qPCR

CD4+ T cell subsets analyzed

Naïve: mature, antigen inexperienced T cells, reside in blood and lymphoid tissue

Effector Memory (EM): antigen experienced, reside in blood and effector tissues

Central Memory (CM): antigen experienced, long-lived pool of precursors for additional memory and effector cells, reside in blood and lymphoid tissue

T follicular helper (Tfh): antigen experienced, promote B cell proliferation and maturation, reside in lymphoid follicles

Analysis and sorting of CD4+ T cell subsets

Lymphocytes

Single Cells

Live cells CD3+ Live Lymphocytes

CD4+ cells

Memory CD4+ cells

Naive CD4+ cells Non-Tfh cells

CM

EM

Tfh cells

Tfh cells

SIV infected cell frequencies: PBMC

SIVsmmE543-infected RM

SIVsmm-infected SMSIVmac239-infected RM

SIV infected cell frequencies: LN

SIVsmmE543-infected RM

SIVsmm-infected SMSIVmac239-infected RM

Why are Tfh cells more prone to SIV infection in RM?

Why are Tfh cells more prone to SIV infection in RM?

SIV+ cells in the GC of lymph nodes

Within folliclesExtrafollicular T cell zone

Trapping of Virions by FDCs

Summary

Different anatomical & cellular viral reservoirs in natural (SM) and non-natural (RM) hosts for SIV

CM CD4+ T cells of RM are 2-10x more frequently infected than SM CM CD4+ T cells – both in PBMC and LN

Frequency of SIV-infected CD4+ Tfh cells is higher in RMs compared to SMs

LN SIV viral burden is greater in RM than SMPreferential infection of Tfh cells in RMs is possibly linked

to increased viral trapping by FDCs Preferential infection of Tfh cells in RM may, in part,

contribute to abnormal antibody responses observed during progressive SIV infection

Acknowledgements

Lab of Molecular Microbiology, NIAID, NIHJason BrenchleyMolly PerkinsLauren CanaryNichole Klatt

AIDS and Cancer Virus Program, Frederick National LaboratoryJake EstesJeff LifsonBrian Tabb

Pathology and Histotechnology Laboratory,Frederick National LaboratoryXing Pei Hao

Lab of Molecular Microbiology, NAID, NIHVanessa Hirsch

NIH Animal CenterHeather CroniseJoanna SwerczekRick Herbert

Division of Infectious Diseases, University of Colorado DenverElizabeth Connick

Emory UniversityMirko PairidiniGuido Silvestri

RM maintain similar overall frequencies of SIV infected naïve, EM, and CM CD4+ T cells as SIV-infected SM

Maintenance of memory Tfh CD4+ T cell subset in SIV+ RM