track a basic science report

www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013

TRACK A

BASIC science report


TRACK A : BASIC scienceTHE TEAM

Nichole KlattUSA

Clovis PalmerAustralia

Uriel Moreno-NievesMexico

and behind the stage….the IAS people !!


TRACK A : the KEY words

• Immune activation and Inflammation• Mucosal infection• Acute infection• Myeloid cells• Restriction factors• Reservoir• Recovery

SIV

mod

el :

path

ogen

inc

vs n

on p

atho

geni

c

HIV

Klatt et al. Immunol Rev 2013

Microbial translocation

InflammationCoagulation

Odds of Mortality (4th vs 1st Quartile)(Independent of CD4 count and virus load)

Markers of Inflammation and GI Dysfunction Predict Mortality

%CD38+DR+

%CD57+DR+

T cells

Innate activation is a stronger predictor of death than T cell activation

OTHER markers (IP10, CD163, et al) to add to

(HUNT)

Monocyte cellular phenotypes are independently linked to IL-6, CRP and D-dimer

Monocyte Phenotype (%) OR (95% CI) for CAC Progression* p-valueCD14+/CD16+ 1.65 (1.08, 2.52) 0.02CD14dim/CD16+ 1.36 (0.98, 1.88) 0.06CD14var/CD16+ 1.69 (1.12, 2.54) 0.01*CAC Progression defined as ‘B’ or ‘C’ above; OR per 1% greater frequency of given phenotype, adjusted for age, gender, race, smoking, diabetes, hepatitis B or C co-infection, current CD4 count, HIV RNA <400 copies/mL, and cholesterol and blood pressure lowering treatment

Monocyte Activation Independently Predicts Greater 2-yr Coronary Artery Calcium Progression (SUN Study)

I. SERETIROLE In CARDIOVASCULAR DISEASE


Myeloid cells matter…..

Dysregulation of Metabolic pathways

Non-communicable diseases

Reservoir of HIVAnd approaches to release

HIV-related dementia

Opportunistic infections

IRIS

Borrowed from Crowe

(Anzinger)

(F. Graziano)

(M.I. Sada-Ovalle)(H.Tran)

The Lymph node : a major player

By T. SchackerLYMPH NODE FIBROSIS in HIV infection

Start ARV

Pirfenidone (anti-fibrotic) therapy in macaque is associated with preservation of LN CD4 T cell population

(Schacker)


Probiotics + ARV in SIV infected macaques decreased fibrosis and enhanced CD4 reconstitution

In the gut : fibrosis and CD4 loss N. Klatt


ACE/ARBsSchacker/UMHatano/UCSFSandler/ACTG

Anti-IL-6Lederman/CWRU

RifaximinTenorio/ACTG

Hsue/UCSF

SevelamerSandler/ACTG

MesalamineSomsouk/UCSF

StatinsNixon/ACTG

MethotrexateHsue/ACTG

ChloroquineJacobson/ACTG

IsotretinoinKwon/ACTG

CLINICAL trials to decrease immune activation: Many approaches are in the field

or are planned

Courtesy of S. Deeks & P. Hunt, with permission from M.P.


Attention to unexpected results: peg-IFN alpha vs. type I IFN R antagonist

MACAQUE STUDY interphering with type I IFN pathway to protected from disease.

Although administration of IFNa delayed acquisition of the infection, both treatments

accelerated progression to disease. D. Douek


Where is the virus….hidden ?• Full RNA transcription (highest levels) is associated with

CD4 down regulation in vivo (Koup)• In lymph nodes of SIV loss of T cell in paracortical area and

expansion of in germinal center. The GC CD4 cells are highly infected. >> GC hypertrophy >> higher immune activation (Koup)

• T Follicular cells are supporting HIV infection and replication.

• Tscm (memory stem cells, long-lived, pluripotent) are infected but do contribute little to the total reservoir (Silvestri and Lichterfeld)

CD4+ TSCM are numerically preserved during BOTH pathogenic and nonpathogenic SIV infections.

G. SILVESTRI

Robust levels of CD4+TSCM infection in vivo are observed in SIV-infected RMs but not in SIV-infected SMs.


Tscm in HIV infection

• Tscm are a cell reservoir with the highest DNA content compared to other T cell subsets. The contribution to the total reservoir is not high, as Tscm represent 2-3% of all T cells, BUT is consistent in time.

Can the virus in Tscm be eradicated ?• Susceptibility of TSCM and TCM to HDACi in vitro but in vivo not

clear.• Beta-catenin inhibitors induce differentiation of TSCM and TCM

into more short-lived CD4 T cell subsets.• Evidence for synergistic activity of HDACi and beta-catenin

inhibitors for increasing chromatin acetylation and HIV-1 reactivation.

M. Lichterfeld


When limit the virus ? SPARTAC (John Frater)

VISCONTI (French study group)

RV254 (Jintanat Ananworanich)

Boston cohort (Marcus Altfeld)

ELITE controllers (Olivier Lambotte)

…….

ANRS workshop

THE EARLIER THE BEST !! ??


How to regulate the virus ?New players and old ones with new functions

• BST2/Tetherin (isoforms): promote HIV release, but interphere with pDC antiviral responses (control INFa release). (Cohen)

• ERAP2 (ER aminopeptidase) : trims peptides for optima MHC1 presentation (haplotypes) : different resistance to HIV infection. (Salle)

• CTP2 : multifunctional cellular factor establishment of latency/HDAC and inhibits viral reactivation/P-TEFb (Rohr. HIVCure)

• p21 : repression of the dNTP biosynthetic enzyme RNR2 to restrict HIV reverse transcription in macrophages (Pancino)

• SAMHD1 : is inhibited by infected DC/Tcell crosstalk (Su) and in Elite controllers (Martin-Gayo)

• LEDGF/p75 and TNPO3 : altered HIV replication (pre and integration) in mDC of elite controllers (Martin-Gayo)

OTHERS to come…. Potential targets for new therapies

HIV PREVENTION Symposium Vaccine Efficacy Trials

NOTE: Phambili (HVTN 503) began to explore a regime similar to STEP in South Africa (not included).

No

From Diffenbach

>12Abs

1

>25

>25>5

gp41

gp120

viralmembrane

MPER(10E8)CD4bs

(VRC01)

V3 / V4 / glycans(cluster of targets:

PGT120s, PGT130s)

Glycans(2G12)

V1/V2 / glycans(PG9)

V3/CD4i(3BC176)2

N332 Abs

HIV is vulnerable : bnMAbs show sites

that could be targeted by vaccine-induced

Abs

Rational HIV immunogen design to target specific germline B cell receptors.

Jardine, Science 2013

“N322 gp120 moAbs series“ ….. PGT121D. BurtonGermline sequencing

Neutralization strength (IC50)

Neu

tral

izatio

n Br

eath

(n o

f iso

late

s)

100%

low high

PGT121

Precursor

Precursor

? Do we need the most potent or is a pool of intermediate sufficient ?

Klatt et al. Immunol Rev 2013

To complete the gaps

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