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B5 intergrin main contributor to hiv


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B5 intergrin main contributor to hiv

  1. 1. ß5 Integrin Is the MajorContributor to the åv Integrin-Mediated Blockade of HIV-1ReplicationDiego Herrera
  2. 2. What is HIV?• Retrovirus which infects lymphocytes º Helper T-cells º Macrophages º Dendritic Cells• Transmission º Sexual Intercourse º Blood products º Mother-to-child º Multiple Infection• Diagnosis º Enzyme-Linked Immunsorbent Assay (ELISA), then confirmed by Western Blot
  3. 3. History• Originated from non-human primates in sub- Saharan Africa º Zoonosis in West-Central Africa in late 19th or early 20th century• Simian Immunodeficiency Virus (SIV) º Infects chimpanzees º SIV evolved to HIV-1 º Bushmeat hunters and vendors commonly acquire SIV
  4. 4. Epidemic
  5. 5. Antiretroviral Therapy and itsImpact on the HIV-1/AIDSPandemic• Perception has changed from untreatable to having approved drug therapies º Retrovir® (zidovudine, AZT)• Challenges º Continued pace of new infections worldwide º Role of pre-exposure prophylaxis (PrEP) º Drug resistance and viral genetic diversity º Cross species transmission º Side-effects (cardiovascular and toxicity)
  6. 6. Nucleotide ReverseTransciptase Inhibitors (NRTIs)• Foundation of antiretroviral drugs º Competitive inhibition and chain termination against the HIV-1 DNA polymerase - Mammalian DNA polymerases contain enzyme, polymerase gamma - Replicated mitochondrial DNA• Biases slowed down drug development º No retroviruses associated with human disease º If they did exist, minor role in public health
  7. 7. Azidothymadine (AZT)
  8. 8. AZT Resistance
  9. 9. Timeline
  10. 10. Biosynthesis
  11. 11. Overview• Influence of different åv-coupled ß integrins in HIV-1 replication in macrophages• Integrin-mediated blockade of HIV-1 replication º Specific monoclonal antibodies (mAbs) º Small arginine-glycine-asparic acid (RGD) mimetic compounds º RNA interference• Role of integrin dimmer åß5 in HIV-1 infection of macrophages
  12. 12. Integrins• Family of transmembrane receptors º Mediate cell adhesion cells to extracellular matrices º Control complex cell functions - Proliferation - Differentiation - Survival - Regulation of gene expression - Promote viral replication
  13. 13. Monocytes and Macrophages• Targets of HIV-1 infection and multiple aspects of viral pathogenesis º Trojan Horse - Differentiation of monocytes to macrophages - Integrins are upregulated, contolling differentiation - Macrophages become more susceptible to HIV-1 infection
  14. 14. NF-kB-dependent HIV-1Transcription• Inhibition by åv integrin-mediated adhesion and signaling in HIV-1 infection of macrophages º Mediated by MAPK signalling cascade º Revealed significant role of åv integrin
  15. 15. Inhibition of åV Integrin
  16. 16. Results
  17. 17. ß-integrin expression in MDMs 3 d Post-differentiation
  18. 18. ß-integrin expression in MDMs Relative mRNA expression
  19. 19. Inhibition of HIV-1 replication inpresence of ß-integrin
  20. 20. Inhibition of HIV-1 replication inthe presence of åvß3 and åvß5
  21. 21. Anti-viral Affinity andCorrelation
  22. 22. ß5 Integrin Blocked by siRNA
  23. 23. Non-Targeting siRNA siß3 siß5
  24. 24. siRNA
  25. 25. Nobel Prize
  26. 26. RNA Interference• Discovered by Andrew Z. Fire and Craig C. Mello º Gene silencing by double-stranded RNA º Degrades mRNA from a specific gene º Mechanism - Activated by dsRNA in cells - Activates biochemical machinery which degrades mRNA with genetic code identical to dsRNA - Gene is silenced and no encoded protein is made• Research º Used to study function genes º Will be used in future drug therapies
  27. 27. siRNA Pathway
  28. 28. siRNA Therapeutic Reagent Target Non-Target
  29. 29. Video
  30. 30. Companies
  31. 31. Conclusions• Monocytes and macrophages play a major role in HIV transmission in all stages of disease and infection º Macrophages important cellular reservoir for the virus• Cell-to-cell contacts, cell adhesion to the substrate and cell differentiation state enhance HIV replication
  32. 32. Conclusions (cont.)• Downregulation of ß5 integrin leads to the blockade of HIV replication in MDMs º Demonstrated by RNA interference - Proven as useful too specifically test effect of a single gene or protein - Clearly distinguished between ß3 and ß5 functions• Integrin Antiretroviral Effect º Integrin-triggered signals cause activation and nuclear translocation of MAPKs º However, there are other signals (i.e PI3K activation and downstream phosphorylation)
  33. 33. Conclusions (Cont.)• siRNA Therapuetics º Temkira - Zaire Ebola Virus (ZEBOV) - Targeted RNA Polymerase L Protein - Delivered in stable-nucleic acid-lipid particles · Complete post-exposure treatment against ZEBOV in non- human primates · Model to treat ZEBOV-induced haemorrhagic fever · May be useful for other viral infections
  34. 34. Questions