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TRACK A BASIC science report

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

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TRACK A BASIC science report

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  1. TRACK A BASIC science report

  2. TRACK A : BASIC science THE TEAM Nichole Klatt USA Uriel Moreno-Nieves Mexico Clovis Palmer Australia and behind the stage….the IAS people !!

  3. TRACK A : the KEY words • Immune activation and Inflammation • Mucosal infection • Acute infection • Myeloid cells • Restriction factors • Reservoir • Recovery SIV model : pathogenincvs non pathogenic HIV

  4. Klatt et al. Immunol Rev 2013

  5. Markers of Inflammation and GI Dysfunction Predict Mortality (HUNT) Microbial translocation Inflammation Coagulation %CD38+DR+ T cells %CD57+DR+ Odds of Mortality (4thvs 1st Quartile) (Independent of CD4 count and virus load) Innate activation is a stronger predictor of death than T cell activation OTHER markers (IP10, CD163, et al) to add to

  6. Monocyte cellular phenotypes are independently linked to IL-6, CRP and D-dimer Monocyte Activation Independently Predicts Greater 2-yr Coronary Artery Calcium Progression (SUN Study) ROLE In CARDIOVASCULAR DISEASE I. SERETI

  7. Myeloid cells matter….. Reservoir of HIV And approaches to release Non-communicable diseases (F. Graziano) Dysregulation of Metabolic pathways HIV-related dementia (Anzinger) IRIS Opportunistic infections (H.Tran) (M.I. Sada-Ovalle) Borrowed from Crowe

  8. The Lymph node : a major player

  9. LYMPH NODE FIBROSIS in HIV infection By T. Schacker

  10. Start ARV Pirfenidone(anti-fibrotic) therapy in macaque is associated with preservation of LN CD4 T cell population (Schacker)

  11. Probiotics + ARV in SIV infected macaques decreased fibrosis and enhanced CD4 reconstitution In the gut : fibrosis and CD4 loss N. Klatt

  12. 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.

  13. 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 IFNadelayed acquisition of the infection, both treatments accelerated progression to disease. D. Douek

  14. 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 >> higherimmune activation (Koup) • T Follicular cellsare 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)

  15. CD4+ TSCM are numerically preserved during BOTH pathogenic and nonpathogenic SIV infections. Robust levels of CD4+TSCM infection in vivo are observed in SIV-infected RMs but not in SIV-infected SMs. G. SILVESTRI

  16. Tscm in HIV infection M. Lichterfeld • 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.

  17. When limit the virus ? SPARTAC (John Frater) VISCONTI (French study group) RV254 (JintanatAnanworanich) Boston cohort (Marcus Altfeld) ELITE controllers (Olivier Lambotte) ……. ANRS workshop THE EARLIER THE BEST !! ??

  18. 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 : multifunctionalcellular factorestablishment 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: isinhibited 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

  19. HIV PREVENTION Symposium Vaccine Efficacy Trials No NOTE: Phambili (HVTN 503) began to explore a regime similar to STEP in South Africa (not included). From Diffenbach

  20. HIV is vulnerable : bnMAbs show sites that could be targeted by vaccine-induced Abs V1/V2 / glycans (PG9) >12 Abs 1 2 Glycans (2G12) >25 N332 Abs V3 / V4 / glycans (cluster of targets: PGT120s, PGT130s) >25 V3/CD4i (3BC176) gp120 MPER (10E8) >5 CD4bs (VRC01) gp41 viral membrane

  21. “N322 gp120 moAbs series“ ….. PGT121 D. Burton Germline sequencing 100% PGT121 Precursor Precursor Neutralization Breath (n of isolates) Rational HIV immunogen design to target specific germline B cell receptors. Jardine, Science2013 low high Neutralization strength (IC50) ? Do we need the most potent or is a pool of intermediate sufficient ?

  22. MORE BASIC RESEARCH To complete the gaps Klatt et al. Immunol Rev 2013

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