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AsierSáez-Cirión, PhD

Unité HIV Inflammation et Persistance

Institut Pasteur

HIV-1 infection:

When the virus and the host

play hide and seek

Joseph et al Nat RevMicrob2015 13,414425

HIV-1 infection starts with transmission of limited number of founder viruses

Several factors determine the selection

of the founder viruses: -Sensitivity to autologous antibodies -Sensitivity to IFN -Level of glycosylation -Fitness to infect target cells

HIV-1 replicationcycle: multipletargets for

antiretroviral therapy However antiretroviral therapy does not target the integrated provirus

AdaptedfromA Fauci

HIV persistsin cellularreservoirsdespitedurable

antiretroviral treatment

Cellsusceptibilitytoinfection

ResistancetoHIV

inducedapoptosis

Escape immune

surveillance

Halflife

Turnover

Establishment of HIV reservoir is a multifaceted process

Restriction

factors

APOBEC3 proteins

TRIM5ɲproteins

BST-2/Tetherin

MX2

SAMHD1

Dependency

factors

Brassand al., Science. 2008, 319:921-6

Balance between restriction and

dependency factors

Cellsusceptibilitytoinfection

SurvivaltoHIV infection

ResistancetoHIV

inducedapoptosis

Escape immune

surveillance

Halflife

Turnover

Establishment of HIV reservoir is a multifaceted process

VinuesaJ Clin Invest.2012

FDC cytokines Îenhance HIV replication in

TFH cells and increase proliferative rate of

infected TFH cells viral persistence, since germinal centers are relatively devoid of cytolyticCD8+T cells.

Finziet al. Cells 1997

Cellsusceptibilitytoinfection

SurvivaltoHIV infection

ResistancetoHIV

inducedapoptosis

Escape immune

surveillance

Cell Persistence

Halflife

Turnover

Establishment of HIV reservoir is a multifaceted process

Survivaland cellproliferation

Viral particles are released by infected cells

that persist by homeostatic proliferation

Adapted from Shenand Siliciano. JACI 2008

Two models to explain persistence on cART

LowlevelHIV replication

cARTdoesnotcompletelyblockviral replication(andinparticularcell-to-cell transmission)

Survivaland cell proliferation

HIV infects cells from the immune system that contribute to spread and persistence

T cells (47,

CCR6+)

macrophages

T cells

Microglial cells

Follicular DCs

T Follicular Helper

hematopoietic progenitor cells

CD4+T lymphocytes

(incluidngHIV-specificcells)

Monocytes/macrophagesDendriticcells

HIV replication is compartmentalized

Santangeloet al Nat Methods 2015

HaaseNature 2010

Spread and establishment of reservoirs is a fast process

Log RNA in plasma

cARTday 3 p.i.

Whitney et al Nature 2014

SIV reservoir established within 3 days?

Development of Immune responses during

acute HIV-1 infection

Initial seeding of the

reservoir

Innate

response Concomitant establishment of viral reservoirs and development of immune responses

Adapted from McMichael et al Nat Rev Immunol2010

M.Altfeld, et al, 2011, Nat Rev Immunol

Very early events and innate immunity

-Innate immunity constitutes a first barrier of defense against HIV infection: NK cells have direct antiviral activity and promote adaptive immunity

Type I IFN production by pDCs

-Early and strong cytokine response may contribute to viral dissemination, establishment of reservoir and may decide the fate of immune responses

McMichael et al 2010 Nat Rev Immunol

TheCD8+ T cellresponse contributesto partiallycontrol

HIV infection

CTL CD4

Haase, Nature, 2010, 464, 217-223

CD8+Tcellsproducesolubleanti-HIVfactors

cellsthroughcytotoxicmechanisms. -CoincidencebetweentheappearanceofHIV specificCD8+Tcellsandcontrolofprimary infection. -DepletionofCD8+TcellsduringSIVinfection leadstoincreasedviralload. -AssociationbetweenClassIHLAsandlevelof viremia

AntibodiesagainstHIV: multiplewaysto tacklethe

infection

H MouquetTrends Immunol2014

Ultimatelythesedefensesare inefficientto control thevirus

Initial seeding of the

reservoir

Innate

response

Hennet al, PLoSPath, 2012

Virus evolves to escape immune responses1% of variability/yearin eachinfectedindividual

Global flu

HIV one patient

HIV in Congo

Viral diversity 1996

Adapted from R Weiss Nature 2003

and B KorberBr Med Bull 2001 Inefficientcontrol of infectionleads to exhaustionof immuneresponses and damageof lymphoidstructures

Freeman et al JEM, 2006, 203, 2223-2227

Loss of organized B cell follicles

Disruption of reticulinnetwork in T cell zone

Estes et al. Seminars Immunol2008, 20, 181-86

Inflammation

Dyslipidemia

Hypercoagulation

Microbial

translocation

HIV-associated fat

Metabolic syndrome

HIV production

HIV replication

CMV

Excess pathogens

Loss of regulatory

cells

Co-morbidities

AgingSteven Deeks, IAS 2013, KL

HIV associatedchronicinflammation

Immuneactivationand HIV pathogenesis

A Fauci. 30 yearsof HIV infection. 2013

Differencesin viral set

points, rates of CD4 T cellsdecline, levelsof viremia, inflammation/immune activation, emergenceof

CTL escape mutants or

developmentof opportunisticinfections Extensive interindividualvariabilityin responseto HIV (susceptibilityto virus, transmission and disease)

A smallproportion of HIV-1 infectedpeople

show "naturalresistance» to infection (HESN) or to diseaseprogression (HIC,LTNP) All the same, but all different in response to HIV

F Barré-Sinoussi

Adapted from G. Silvestri

DistinctHIV/SIV infectionoutcomes

Immune

activation

Noel et al AIDS 2014

Threestepsto control HIV-1 infection

1-Limit viral reservoirs

2-Develop efficient mechanisms to control viral

rebound

3-Restrain immune activation/inflammation

HIV/AIDS: an outstanding global health problem

~ 36.9 million people living with HIV cARTintroduction changed the face of the epidemic, however: -2.0 million new infections/year -1.2 million deaths/year -60% of patients still in need of life-long cART

Patients request alternative strategies

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