Clinical Application of Stem Cells in HIV
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Clinical Application of Stem Cells in HIV

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Proposal for application of stem cell therapy in the HIV treatment. This was made for a graduate stem cell course I completed at UCI.

Proposal for application of stem cell therapy in the HIV treatment. This was made for a graduate stem cell course I completed at UCI.

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Clinical Application of Stem Cells in HIV Presentation Transcript

  • 1. Hematopoietic Stem Cell Therapy for Human Immunodeficiency Virus Ahmed Ibrahim March 6, 2007
  • 2. Overview
    • Human Immunodeficiency Virus-1
    • 2. Pathology of AIDS and Effect on Hematopoeisis
    • 3. Current Treatments and Challenges
    • 4. Proposal Rationale and Approach
    • 5. Promises and Challenges
    • 6. Prospective Directions
    • 7. Questions?
  • 3. 1. Human Immunodeficiency Virus
  • 4. Human Immunodeficiency Virus-1 (HIV-1)
    • HIV-1 is a single stranded RNA virus.
    • Surface proteins include gp120, a highly conserved docking glycoprotein.
    • Attachment proteins is mainly mediated by gp41 transmembrane glycoprotein.
    • Contains reverse transcriptase enzyme in the interior of the virus.
    • Integrase used to integrate viral DNA in host genome.
  • 5.
    • gp120 binds CD4+ T cells as docking mechanism (attachment)
    • Viral fusion is mediated through gp41 transmembrane protein
    • Reverse transcriptase converts ssRNA to dsDNA
    • dsDNA+integrase exported to nucleus
    • viral genome is incorporated into the host genome.
    • Viral polyproteins expressed and cleaved by proteases
    • nonlytic budding of virions occurs
  • 6. 2. Pathology of AIDS
  • 7. AIDS: Acquired Immunodeficiency Syndrome Collection of symptoms and infections caused by specific damage to the immune system Caused by Human Immunodeficiency Virus Single Stranded RNA Virus (retroviridae) Stage I: asymptomatic Stage II: Minor mucocutaneous manifestations and recurrent upper respiratory tract infections Stage III: includes unexplained chronic diarrhea for longer than a month, severe bacterial infections and pulmonary tuberculosis Stage IV: includes toxoplasmosis of the brain, candidiasis of the esophagus, trachea, bronchi or lungs and Kaposi's sarcoma
  • 8. Route of Transmission (per 10,000 incidences) 0.5 Insertive oral intercourse * 1 Receptive oral intercourse * 5 Insertive penile-vaginal intercourse * 6.5 Insertive anal intercourse * 10 Receptive penile-vaginal intercourse * 30 Percutaneous needle stick 50 Receptive anal intercourse * 67 Needle-sharing injection drug use 2,500 Childbirth 9,000 Blood Transfusion
  • 9. Regional HIV and AIDS statistics and features, 2006 TOTAL North America Eastern Europe & Central Asia Latin America South and South-East Asia Sub-Saharan Africa Oceania Western & Central Europe Caribbean East Asia Middle East & North Africa 18 000 [11 000 – 26 000] 84 000 [58 000 – 120 000] 65 000 [51 000 – 84 000] 590 000 [390 000 – 850 000] 2.1 million [1.8 – 2.4 million] 270 000 [170 000 – 820 000] 2.9 million [2.5 – 3.5 million] 0.8% [0.6% – 1.1%] 0.9% [0.6% – 1.4%] 0.5% [0.4% – 1.2%] 0.6% [0.4% – 1.0%] 5.9% [5.2% – 6.7%] 1.0% [0.9% - 1.2%] 4.3 million [3.6 – 6.6 million] 43 000 [34 000 – 65 000] 140 000 [100 000 – 410 000] 860 000 [550 000 – 2.3 million] 2.8 million [2.4 – 3.2 million] 4000 [2300 – 6600] 12 000 [ <15 000] 19 000 [14 000 – 25 000] 43 000 [26 000 – 64 000] 36 000 [20 000 – 60 000] 0.4% [0.2% – 0.9%] 0.3% [0.2% – 0.4%] 1.2% [0.9% – 1.7%] 0.1% [<0.2%] 0.2% [0.1% – 0.3%] 7100 [ 3400 – 54 000] 22 000 [18 000 – 33 000] 27 000 [20 000 – 41 000] 100 000 [56 000 – 300 000] 68 000 [41 000 – 220 000] Adult & child deaths due to AIDS Adult (15 ‒ 49) prevalence [%] Adults & children newly infected with HIV Adults & children living with HIV 24.7 million [21.8 – 27.7 million] 39.5 million [34.1 – 47.1 million] 1.4 million [880 000 – 2.2 million] 1.7 million [1.2 – 2.6 million] 1.7 million [1.3 – 2.5 million] 7.8 million [5.2 – 12.0 million] 81 000 [50 000 – 170 000] 740 000 [580 000 – 970 000] 250 000 [190 000 – 320 000] 750 000 [460 000 – 1.2 million] 460 000 [270 000 – 760 000]
  • 10. Regional HIV and AIDS statistics and features, 2006
  • 11.  
  • 12. Bone Marrow Abnormalities of HIV-1 Infected Patients Suppression of cell growth in the bone marrow (Moses A, Nelson J, Bagby G., 1998) Infection of accessory cells (macrophages, microvascular endothelial cells) result in impairment of the HSC growth network Unable to directly infect hematopoietic stem cells due to: High expression of fas-l and cytokines (ifn-g) inhibits viral invasion of HSC’s (Maciejewski J, Selleri C, Anderson S, Young NS, 1995) A consequence is also a high rate of apoptosis in hematopoietic stem cells (G. Zauli and S. Capitani, 1996) .
  • 13. Clinical Course of HIV-1 Infected Patients
  • 14.
    • Bacterial and Mycobacterial
    • Mycobacterium Avium Complex (MAC, MAI)
    • Salmonellosis
    • Syphilis and Neuroshyphilis
    • Turberculosis (TB)
    • Bacillary angiomatosis (cat scratch disease)
    • Fungal Infections
    • Aspergillosis
    • Candidiasis (thrush, yeast infection)
    • Coccidioidomycosis
    • Cryptococcal Meningitis
    • Histoplasmosis
    • Malignancies
    • Kaposi's Sarcoma
    • Lymphoma --
      • Systemic Non-Hodgkin's Lymphoma (NHL)
      • Primary CNS Lymphoma
    • Protozoal Infections
    • Cryptosporidiosis
    • Isosporiasis
    • Microsporidiosis
    • Pneumocystis Carinii Pneumonia (PCP)
    • Toxoplasmosis
    • Viral Infections
    • Cytomegalovirus (CMV)
    • Hepatitis
    • Herpes Simplex (HSV, genital herpes)
    • Herpes Zoster (HZV, shingles)
    • Human Papiloma Virus (genital warts, cervical cancer)
    • Molluscum Contagiosum
    • Oral Hairy Leukoplakia (OHL)
    • Progressive Multifocal Leukoencephalopathy (PML )
    Opportunistic Infections Linked to HIV infection
  • 15. 3. Current Treatments and Challenges
  • 16. Current Treatments for HIV infection
    • Reverse transcriptase inhibitors
    • nucleoside
    • non-nucleoside
    • Protease inhibitors
    • Fusion inhibitors stop HIV from entering CD4 cells in the first place.
    • Integrase inhibitors
    • Anti-infection Drugs
    • Live Cell Vaccines
    • T cell Vaccines
    • Dendritic Cell Vaccines
  • 17.
    • Long Term Non-progressive patients
    • Robust immune system
    • Fortuitous genetic mutations in CCR5/CXCR4
    • Sensitivity to Ifn's (i.e. ifn- γ )
  • 18.
    • Found patterns of resistance from CD4 T cells of Exposed Uninfected Patients
    • CD4 T cells showed low expression of CCR5 due to heterozygous mutations in CCR5
    • CD4 T cells were more sensitive to β -chemokines than normal CD4 T cells
    • Inhibitory processes included post-viral entry step inhibition
  • 19. 5. Challenges to current approaches
  • 20. Challenges Associated with the HIV Treatments
    • Viral resistance mechanisms to drugs (mutations, evasion)
    • 2. Threat of drug toxicity (i.e. nivirapine, AZT, sulfonamides, etc.)
    • 3. Drug interactions
    • 4. Live cell vaccines provide only one component of several key cellular mediators of immunity (mainly targeted as preventative).
    • 5. Live cell vaccines are, themselves, prone to infection.
  • 21. Rationale of the Therapeutic Approach The main pathology of AIDS is immunodeficiency Poor prognosis not directly related to virus but opportunistic infection Hematopoietic stem cells are the precursors to all immune cells It has been demonstrated that HSC’s can be stably transfected in Cases where mutations/polymorphisms in CXCR4/CCR5 co-receptors have controlled infection exist (Long Term Nonprogressive HIV patients)
  • 22.
    • Transplantation of HSC’s modified with this mutation will intervene in the course of AIDS by:
    • Rescuing the immune response and help defend against opportunistic infections
    • Prevent further entry of the virus into the transplanted cells (gp120/gp40 become obsolete)
    • Virus may lose fitness by failing to enter CD4+ cells or less likely die altogether with the complete depletion of the original host cells.
    Hypothesis
  • 23. Research Approach Phase I 1. Developing transgenic versions of CXCR4/CCR5 that are HIV-1 impermissible. -Sequence analysis of known medical cases of HIV resistance -Development of a library of mutants in a yeast expression system 2. Efficient transfection system for modification of implanted HSC’s 3. Appropriate animal for model for studying the effects of HIV-1 Phase II Testing for long term non-progression in mice transplanted with modified HSC's using both X4 and R5 viral HIV viral types. Probe for modification conditions that would provide the best clinical outcome for infected animals
  • 24. 1. Proposes the transplantation of Modified Hematopoietic Stem cells 2. Gammaretroviral vector for M87o, which encodes an artificial transmembrane molecule which inhibits fusion mediated uptake of the virus with CD4 cells. 3. Successfully transfected gene into hematopoietic stem cells into NOD-SCID mice and sustained expression for one generation.
  • 25.
    • Transfected NOG mice with cd34+ hematopoietic stem cells from Human Cord Blood rather peripheral blood mononuclear cells (PBMC’s)
    • Detected the presence of human lineage lymphoid cells
    • 3. Infected the mice with R5 (CCR5) and X4 (CXCR4) tropic HIV variants
    • 4. Infected mice with X4 and R5 HIV variants
    • 3. Mice began showing symptoms of malaise, wasting, and humoral immunity was already being mounted against antigens of the HIV strains with high viral RNA in the plasma.
  • 26. 6. Prospective Challenges
  • 27. Promises
    • Clinical Perspective
    • Effectively restored immunity to the patient, and prevent opportunistic disease
    • Blocked further infection of the virus
    • Uses the transplanted or the individual's HSC's
    • Extend the lifespan of the patient
  • 28. Prospective Challenges
    • Clinical Perspective
    • Hematopoietic Stem Cells may themselves be subject to high apoptotic conditions of the bone marrow of infected individuals
    • Viral mutations may develop tropisms for other immune cells or go into latency
    • Public Health Perspective
    • Costly
    • Not feasible to manufacture in developing countries where it is needed the most.
    • Not easily distributable
  • 29. Counterchallenges
    • Clinical Perspective
    • Early detection
    • Use of this strategy in conjunction with other therapeutic regimens (i.e. drugs)
    • Public Health Perspective
    • Develop more efficient and cost effective transfection and bone marrow transplant strategies and kits.
    • Invest a majority of these treatments in affected areas rather than marginally affected countries.
  • 30. 6. SIMPLE QUESTIONS ONLY