HIV Therapeutic vaccines
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A review of the HIV Therapeutic vaccination strategies and some of the significat approaches introduced so far.
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HIV Therapeutic vaccines
- 1. HIV Therapeutic vaccines PATHWAYS TO AN EFFECTIVE HIV VACCINE By: Dr. Reza Mozafari
- 2. control/clear HIV from already infected individuals Therapeutic vaccines aim to increase the activity of the body’s natural defenses. reduce the risk of infection in people who are not infected with HIV This process can act rely on activation of the adaptive immune system. There is still no vaccine for HIV Therapeutic vaccines Prophylactic vaccines
- 3. Advantages: Rapid, cost effective proof of concept assessment of efficacy even in small phase I/II trials and less toxicity of treatment. It may be worth to develop even if not fully effective, since it may be used in association with antiretroviral drugs (ART). Ensoli, Barbara, et al. "Challenges in HIV vaccine research for treatment and prevention." Frontiers in immunology 5 (2014): 417. THERAPEUTIC vaccination strategies
- 4. Human Immunodeficiency Virus (HIV) is a deadly and incurable illness impacting millions annually. The progressive depletion and dysfunction of immune system in HIV is related to all components of the immune system like T cells, B cells, NK cells and etc.
- 5. Icosahedral (20 sided), enveloped virus of the lentivirus subfamily of retroviruses. Genetic material consists of two viral strands of RNA found in core surrounded by protein outer coat. Characteristics of the virus
- 6. HIV-1 Is found worldwide Is the main cause of the worldwide pandemic HIV-2 Is mainly found in West Africa, Mozambique and Angola. Causes a similar illness to HIV-1 Less efficiently transmissible rarely causing vertical transmission Less aggressive with slower disease progression The basic biology of the HIV
- 7. Group specific antigen (gag) Is a single gene responsible for the coding of four proteins, p6, p7, p17, and p24, all related to internal structural or core functions to the virus. Wang, Binghe. Ed. Nouri Neamati. Vol. 9. John Wiley & Sons, 2011.
- 8. Polymerase (pol) gene encodes three main proteins responsible for the reverse transcriptase, protease, and integrases enzymes. Wang, Binghe. Ed. Nouri Neamati. Vol. 9. John Wiley & Sons, 2011.
- 9. Envelope (env) Encodes for the exterior viral proteins. Making use of a host cell enzyme Furin, the fusion protein gp160 coded for my env, is cleaved into two smaller subunits, gp120 and gp41.
- 10. Transactivator The purpose of a transactivator is to selectively increase or decrease the rate of gene expression. The three produced by HIV are transactivator of transcription (tat), regulator of virion (rev), and viral protein-r (vpr). Wang, Binghe. Ed. Nouri Neamati. Vol. 9. John Wiley & Sons, 2011.
- 11. Regulatory factors Three other miscellaneous regulatory factors are also present within HIV, viral infectivity factor (vif), negative regulatory factor (nef), and viral protein-u (vpu) Wang, Binghe. Ed. Nouri Neamati. Vol. 9. John Wiley & Sons, 2011.
- 12. Red Queen hypothesis Mutability escape the immune system rapidly evolve drug resistance circumvent vaccination strategies Error-prone viral replication APOBEC3 cytidine deaminases (G>A hypermutation) How is HIV different from other viruses?
- 13. Bette T. Korber et al. J. Virol. 2009;83:8300-8314 Conserved & immunogenic sequences Vulnerable “Achilles heel” regions!
- 14. If CCR5 is not expressed on their surface, HIV infects them with lower efficiency. SB-728 for HIV/AIDS Sangamo BioSciences (Richmond, CA, USA) copy
- 15. S P Indicating sulfate and phosphate moieties Showing palmitoylation of C moieties DRYLAVVH sequence Mutation in this area reduces ligand binding and severely affects the functional response of the receptor. CCR5 protein structure Mulherin,StephanieA.,etal.Aids17.3(2003):377-387.
- 16. An ex vivo gene therapy approach by which CD4+ T cells drawn from HIV- infected patients are modified ex vivo to disrupt the CCR5 gene in autologous CD4+ T cells, expanded, and reinfused to the patient. The complexity and costs of this approach, together with serious safety issues represent a major disadvantage. Gu, Wan-Gang. Trends in biotechnology 33.3 (2015): 172-179.
- 17. Dr. Barbara Ensoli, has focused on Tat, a key HIV regulatory gene and its protein product, Tat, as a vaccine candidate. In the absence of Tat, the virus is still infect the cell, however it does not replicate. The immunogenic regions of Tat are conserved among the different HIV- 1 Anti-Tat antibodies Activating transcription of HIV Trans-Activator of Transcription
- 18. Changing enzymatic activity Tat regulates the enzymatic activity of immunoproteasome Haynes,BartonF.,etal.NewEnglandJournalofMedicine 366.14(2014):1275-1286.
- 19. Tat Inhibits NKs HIV Tat was found to be able to inhibit the activities of NKs, especially lowering the abilities of NK on releasing IFN-gamma and splitting DCs via a direct NK-DC contact. Haynes, Barton F., et al. New England Journal of Medicine 366.14 (2014): 1275-1286.
- 20. In HIV infection individuals, T cell hyperactivation is linked to the exhaustion of T cell pool in vivo and might promote the progress of disease, which therefore is viewed as a typical marker for predicting the AIDS progression. Promots gene transcription T cell hyperactivation Haynes,BartonF.,etal.NewEnglandJournalofMedicine 366.14(2014):1275-1286.
- 21. Env-specific antibodies would prevent entry of the virus into cells. If successful, the vaccine would provide sterilizing immunity, which protects the vaccinated person from becoming infected with HIV. Most of the efforts in HIV vaccine development have focused on using HIV's Envelope protein (gp120 or Env) in vaccines, but the results have been largely disappointing.
- 22. E-gp120 (Abzentek) Dr. Sudhir Paul introduced the new concept of electron charging of the HIV glycoprotein, gp120. The idea comes from long term survivors (LTS) Lupus patients who can control HIV infection with no therapeutic agents, while, usually the virus escapes the immune system rely on its mutabilitythus, The virus is enable to develop resistance to the BNABs.
- 23. The linear CD4 binding site epitope composed of gp120 residues 421–433 (C-LIN) is vulnerable to antibodies because of its mostly conserved. Karle, Sangeeta, et al. Aids 18.2 (2004): 329-331.
- 24. Rare innate antibodies that recognize the native C-LIN conformation with sufficient specificity and strength neutralize diverse HIV strains. Immunogen BCRs IgM CSR recognition Poor neutralizing! gp120 IgG Planque, Stephanie A., et al. AIDS (London, England) 28.15 (2014): 2201. C-LIN
- 25. Naturally occurring nucleophilic sites expressed by the IgM form a peptide bond that is degraded by an activated water molecule during the proteolysis reaction. The conventional vaccination induce immature antibodies of the IgM class that are too large to penetrate the viral coat and make contact with the c-LIN region. Moreover, the virus has developed a mechanism to suppress the CSR events, and thus, IgG directred to C-LIN are not formed.
- 26. Suhdir Paul suggests: Nonhydrolyzable polypeptide analogs containing the strongly electrophilic phosphonate group (E-gp120) thus; bind secreted IgMs and IgM+ BCRs covalently instead of being catalytically consumed then, class-switched IgGs against C-LIN which is the irreversible covalent complexes with gp120 and proceeded to hydrolyze gp120.
- 27. These properties enhance the BNAB potency and permit more efficient neutralization of HIV.
- 28. Thank you.
Editor's Notes
- The development of an HIV vaccine is a crucial component required to bring the HIV/AIDS epidemic to an end. By introducing a part of the virus or an inactive virus into the body, the immune system reacts by producing antibodies. If, years later, the virus enters the organism, these antibodies will recognize and destroy it.
- Vif works to interrupt a main human antiviral protein, APOBEC, by targeting it for degradation by the bodies own immune system. Nef decreases the expression of MHC surface protein signals of the host cell, making it less likely to be marked for degradation by the immune system, and thereby increasing the chances of virion survival. Vpu is involved in one of the final step of virion production, the budding of the virion from the host cell.
- HAART, combination therapy, (Highly Active Anti-Retroviral Therapy) is a customized combination of different classes of medications that a physician prescribes based on such factors as the patient’s viral load (how much virus is in the blood), the particular strain of the virus, the CD4+ cell count, and other considerations (e.g., disease symptoms). The HIV virus continuously evolves because of the Red Queen hypothesis 44 The high levels of genetic diversity of the HIV-1 virus grant it the ability to escape the immune system, to rapidly evolve drug resistance, and to circumvent vaccination strategies. 44 the expression of host genes may influence the viral mutation rate as is the case of APOBEC3 cytidine deaminases, which can edit the HIV-1 cDNA and produce G-to-A hypermutations . 44 It is also worth mentioning that the high rate of evolution of HIV-1 is not extremely different from that of other RNA viruses such as, for instance, FLUVA or foot-and-mouth disease virus. ++ HIV infection in a single infected individual, as the inaccurate enzymatic machinery of this virus’s replication results in ongoing production of mutant virions. ++ Such an extraordinary degree of genetic diversity 1. an effective HIV vaccine must elicit both mucosal immunity, to contain sexually transmitted virus, and systemic immunity, to contain virus transmitted directly into the bloodstream. 2. HIV is likely transmitted both as cell-free and as cell-associated virus. Therefore, more than a single type of immunity must be elicited by a vaccine if that vaccine is to be effective.
- The regions of HIV with the greatest sequence conservation may not be very immunogenic in naturally infected cells. For example, the most conserved regions in the proteome of HIV are found in Pol, but comparatively few CD8+ T-cell responses recognize Pol epitopes spanning these regions While most regard Gag as conserved and Env as variable, not all regions of Gag aare conserved (only p24 is well conserved throughout), and not all regions of Env are variable.
- HIV, like all viruses, can't make new copies of itself without help. It needs to enter cells and use their machinery to reproduce and spread throughout the body. HIV can only enter certain cells. How does it find the right cells? By special proteins called receptors. Receptors sit on the outside of cells to receive messages and transmit them into the cell. HIV grabs onto cells that have a receptor called CD4. It turns out that CD4 isn't enough. Another protein called CCR5 is needed as well. CCR5, called a co-receptor because it works with CD4. Many people who are resistant to HIV have a mutation in the CCR5 gene called CCR5-delta32. (AR)!
- Palmitoylation is the covalent attachment of fatty acids
- is generated by zinc finger nuclease (ZFN)-mediated modification that disrupts the expression of this key co-receptor for HIV entry and renders cells resistant to HIV infection.
- Finally, Tat is released by acutely infected cells and helps to recruit and activate uninfected cells helping to spread the HIV infection throughout the body. Regulatory genes, including tat, express proteins soon after infection and are essential for virus replication and pathogenesis.
- Proteasomes are protein complexes. The main function of the proteasome is to degrade unneeded or damaged proteins by breaking peptide bonds.
- NKs: a lymphocyte able to bind to certain tumour cells and virus-infected cells without the stimulation of antigens, and kill them by the insertion of granules containing perforin. DCs (Dendritic cells) are the most important antigen presenting cells in vivo. The detailed molecular mechanism indicates that Tat protein impairs CAMK-II (calcium-calmodulin kinase-II) activation on NKs via regulating the expression of crucial factor, LFA-1, which is responsible for activating CAMK-II. The inhibition of CAMK-II activation leads to the block of calcium influx in NK cells, therefore decreasing the secretion of perforin, granzymes and IFN-γ, eventually reducing the extension of NK/DC contacts.
- Tat regulates T cell hyperactivation. Extranuclear Tat activate phosphatidylinositol kinase to make the phosphorylation of complex of NF-κB and IκB, leading to NK-κB translocate into uncleus. Acetylation of NF-κB by P300 starts the activation of NF-κB and promots the gene transcription. In contrast, SIRT1 deacetylates NF-κB and inhibit its activation. Tat acted as the inhibitor of SIRT1 can indirectly improve the acetylation level of NF-κB and activate its function, resulting in T cell hyperactivation.
- As an epitope for CD4, there is a linear binding site in gp120 called CLIN which is mostly conserved.
- An immunogen is an antigen or any substance that may be specifically bound by components of the immune system (antibody, lymphocytes). to IgM+ B-cell receptors (BCRs) Immunogen + BCRs, initiates B-cell antibody responses. Small CLIN-directed reversibly-binding Immunoglobulin class switching (CSR), from the isotype IgM to the isotype IgG.
- Normally, the IgM forms a nucleophilic peptide bond that it is not very stable and may be hydrolyzed by an activated water molecule.