track a basic science report
DESCRIPTION
TRACK A BASIC science report. TRACK A : BASIC science. THE TEAM. Nichole Klatt USA. Uriel Moreno-Nieves Mexico. Clovis Palmer Australia. and behind the stage….the IAS people !!. TRACK A : the KEY words. Immune activation and Inflammation Mucosal infection Acute infection - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/1.jpg)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
TRACK A
BASIC science report
![Page 2: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/2.jpg)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
TRACK A : BASIC scienceTHE TEAM
Nichole KlattUSA
Clovis PalmerAustralia
Uriel Moreno-NievesMexico
and behind the stage….the IAS people !!
![Page 3: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/3.jpg)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
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
![Page 4: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/4.jpg)
Klatt et al. Immunol Rev 2013
![Page 5: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/5.jpg)
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)
![Page 6: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/6.jpg)
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
![Page 7: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/7.jpg)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
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)
![Page 8: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/8.jpg)
The Lymph node : a major player
![Page 9: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/9.jpg)
By T. SchackerLYMPH NODE FIBROSIS in HIV infection
![Page 10: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/10.jpg)
Start ARV
Pirfenidone (anti-fibrotic) therapy in macaque is associated with preservation of LN CD4 T cell population
(Schacker)
![Page 11: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/11.jpg)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
Probiotics + ARV in SIV infected macaques decreased fibrosis and enhanced CD4 reconstitution
In the gut : fibrosis and CD4 loss N. Klatt
![Page 12: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/12.jpg)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
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.
![Page 13: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/13.jpg)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
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
![Page 14: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/14.jpg)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
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)
![Page 15: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/15.jpg)
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.
![Page 16: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/16.jpg)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
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
![Page 17: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/17.jpg)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
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 !! ??
![Page 18: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/18.jpg)
www.ias2013.org Kuala Lumpur, Malaysia , 30 June - 3 July 2013
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
![Page 19: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/19.jpg)
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
![Page 20: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/20.jpg)
>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
![Page 21: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/21.jpg)
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 ?
![Page 22: TRACK A BASIC science report](https://reader035.vdocument.in/reader035/viewer/2022062501/5681653b550346895dd7bd6e/html5/thumbnails/22.jpg)
Klatt et al. Immunol Rev 2013
To complete the gaps
MORE BASIC RESEARCH