TALENTS UP crovella sergio 20_05_2013
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HIVIT_GWAS - Immuno-therapy in HIV positive patients: a genomic approach - by Sergio Crovella

HIVIT_GWAS - Immuno-therapy in HIV positive patients: a genomic approach - by Sergio Crovella

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TALENTS UP crovella sergio 20_05_2013 Presentation Transcript

  • 1. HIVIT_GWASImmuno‐therapy in HIV positive patients: a genomic approachSERGIO CROVELLA PhDcrovelser@gmail.comOutgoing FellowshipBiotechnologies and Diagnostics
  • 2. ORIGIN OrganisationChildren Hospital BurloGarofolo, TRIESTE, ITALYHOST OrganisationInsituto de MedicinaIntegral Prof. Fernando Figueira, RECIFE, BRAZIL
  • 3. HIV VaccinesObtaining an HIV vaccine has been one of the biggest challengesof this century. To date numerous clinical trials have beenconducted to test candidate products as prophylactic vaccine. Currently, about 20 clinical trials are underway, most protocolsfor Phase I.
  • 4. Innate immunity genes and patients responseto Denditric cell‐based HIV immuno‐treatment 
  • 5. • Age: 18 to 41 years (median 25)• Gender/contamination :male/homosex. 2; female/heterosex. 16.• Seropositive for 13 to 65 ms (median 24.5)• Never treated:15 pts /Treated during pregnancy for 3 ms: 3 pts• CD4 T‐cells : 270 ‐1.009/µl ( median,523)         • Plasma viral load: 11.000 to 300.000/ml (geometric mean, 48.400; median, 37.600)Characteristics of the 18 patients
  • 6. The best patient
  • 7. The Host Genome
  • 8. We studied the “innate immune genome” of weak/transient responders (WTR) and durable responders (DR) HIV infected patients, enrolled in the study of Lu et al. in order to understand the reasons of the success or not of the DC vaccine and its relationships with the host innate immunity genome
  • 9. SNPs selection: SNPBrowser, HapMap, QuickSNP, Tagger• 149 INNATE IMMUNITY genes, 768 SNPs• 1) non‐synonymous coding SNPs (nsSNPs), thatinclude a group of SNPs having the highest impact on phenotype due to their potential to directlyaffect the structure, function and interactions ofexpressed protein• 2) Tag SNPs, which represent a subset of SNPscapturing most of the haplotype diversity of eachhaplotype block or gene‐specific region. Illuminas GoldenGate Assay
  • 10. • NOS1 Nitric Oxide (NO) is a pro‐inflammatory and antiviralmolecule, produced bymonocytes and  DCs duringHIV infection• MBL role in HIV infection is still debated, since high levels of serum MBL are usually associated with a good virological response, but some authors also showed that MBL enhances HIV replication, hypothetically through the induction of TNF‐α.
  • 11. ‐1‐0,500,511,5p3 p3‐84 p17 p17‐84 p24 p24‐84 p18‐84 p31‐84 eric"nos1 expression level"00,511,522,533,544,51 2 3 4T0T1T2Dia 62hs48hs T0 T1 T2NOS1 Expression in DC from HIV infected patients
  • 12. Inflammasome and HIV in DC• NALP3‐inflammasome is an innate mechanism, alternative to type‐1 interferon, able to recognize nucleic acids and viruses into cytoplasm and to induce pro‐inflammatory response.• We hypothesized the involvement of inflammasome in the early defence against HIV‐1 and in the fully maturation of dendritic cells• We evaluated the response of dendritic cells pulsed with HIV‐1 in terms of inflammasome activation in 20  healthy donors.• Moreover inflammasome response to HIV was evaluated in 20 HIV infected subjects 
  • 13. • In HC‐DC, HIV‐1 induced higher NLRP3/NALP3 mRNA expression compared to other inflammasome genes such as NALP1/NLRP1 or IPAF/NLRC4 (p<0.001)• This augmented expression was accompanied by CASP1and IL1B increased mRNA levels and by a significant increment of IL‐1 secretion (p<0.05).• Otherwise HIV‐1 failed to activate inflammasome and cytokine production in HIV‐DC.
  • 14. 45 papers published average IF 3.93 +1  PhD Thesis3+ 2 Masters3 grants from CNPq (Brazil)
  • 15. NetworkingHIV‐Latin America NetworkBrazil: Recife, Sao Paulo,Rio de Janeiro, Porto AlegreArgentina: Buenos AiresBolivia: La PazMEEGID Quito 2014Other countries will join The network
  • 16. Immunogenetics and Immunobiology Research Labs IRCCS Burlo Garofolo
  • 17. Europe US networkingMichel Tibayrenc, MD, PhDInfectious Diseases and Vectors,Ecology, Genetics, Evolution and ControlMIVEGEC/IDVEGEC (IRD 224‐CNRS 5290‐UM1‐UM2)IRD Center BP 6450134394 Montpellier Cedex 5 FranceAlfredo Garzino‐Demo Ph.DLaboratory of Virus‐Host Interactions, Division of Basic ScienceInstitute of Human VirologyUniversity of Maryland, Baltimore, USErnesto T.A. Marques Jr., MD, PhD Infectious Diseases and MicrobiologyCenter for Vaccine Research9022 BST3 3501 Fifth AvenuePittsburgh, Pennsylvania 15261
  • 18. Exome‐CHIPS the new frontier
  • 19. DNAH17MDN1CDH23OR5D14PINK1RERGLOR5V1CST2MYH7BFAT3RNF213ADAM30PTCD1ATP5J2‐PTCD1COL12A1TNS1THSD7AMTMR3KIAA1107OR12D3MEGF11NLRP8MKNK1ZNF616SYNE1DSPEPYCNEW TALENTSUPCOMING…
  • 20. TO BE CONTINUED…