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1 Kuala Lumpur, Malaysia, 30 June - 3 July 2013 TRACK A BASIC science report

2 Kuala Lumpur, Malaysia, 30 June - 3 July 2013 TRACK A : BASIC science THE TEAM Nichole Klatt USA Clovis Palmer Australia Uriel Moreno-Nieves Mexico and behind the stage….the IAS people !!

3 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 model : pathogeninc vs non pathogenic HIV

4 Klatt et al. Immunol Rev 2013

5 Microbial translocation Inflammation Coagulation Odds of Mortality (4 th vs 1 st 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)

6 Monocyte cellular phenotypes are independently linked to IL-6, CRP and D-dimer Monocyte Phenotype (%)OR (95% CI) for CAC Progression*p-value CD14+/CD16+1.65 (1.08, 2.52)0.02 CD14 dim /CD16+1.36 (0.98, 1.88)0.06 CD14 var /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. SERETI ROLE In CARDIOVASCULAR DISEASE

7 Kuala Lumpur, Malaysia, 30 June - 3 July 2013 Myeloid cells matter….. Dysregulation of Metabolic pathways Non-communicable diseases Reservoir of HIV And approaches to release HIV-related dementia Opportunistic infections IRIS Borrowed from Crowe (Anzinger) (F. Graziano) (M.I. Sada-Ovalle) (H.Tran)

8 The Lymph node : a major player

9 By T. Schacker LYMPH NODE FIBROSIS in HIV infection

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

11 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

12 Kuala Lumpur, Malaysia, 30 June - 3 July 2013 ACE/ARBs Schacker/UM Hatano/UCSF Sandler/ACTG Anti-IL-6 Lederman/CWRU Rifaximin Tenorio/ACTG Hsue/UCSF Sevelamer Sandler/ACTG Mesalamine Somsouk/UCSF Statins Nixon/ACTG Methotrexate Hsue/ACTG Chloroquine Jacobson/ACTG Isotretinoin Kwon/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.

13 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

14 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)

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

16 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 T SCM and T CM to HDACi in vitro but in vivo not clear. Beta-catenin inhibitors induce differentiation of T SCM and T CM 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

17 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 !! ??

18 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

19 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

20 >12 Abs 1 >25 >5 gp41 gp120 viral membrane 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

21 Rational HIV immunogen design to target specific germline B cell receptors. Jardine, Science 2013 “N322 gp120 moAbs series“ ….. PGT121 D. Burton Germline sequencing Neutralization strength (IC50) Neutralization Breath (n of isolates) 100% lowhigh PGT121 Precursor ? Do we need the most potent or is a pool of intermediate sufficient ?

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

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