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![Page 1: HIV Cure Research Updates Dr. Matthew Marsden Adj. Assistant Professor, UCLA Department of Medicine 9/3/14.](https://reader030.fdocuments.net/reader030/viewer/2022033103/56649d705503460f94a52ba4/html5/thumbnails/1.jpg)
HIV Cure Research UpdatesDr. Matthew Marsden
Adj. Assistant Professor, UCLA Department of Medicine
9/3/14
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http://www.nytimes.com/2011/11/29/health/new-hope-of-a-cure-for-hiv.html?pagewanted=all
http://abcnews.go.com/Health/french-hiv-study-means-hiv-babys-cure/story?id=18741318#.UZFht7VOQrU
http://www.cnn.com/2013/03/18/health/hiv-functional-cure
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• Why is HIV difficult to cure?
• Documented cases of apparent cures
• New gene therapy/transplant approaches
• Additional therapeutic approaches
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Short-lived infected cell
Long-lived infected cell(latently infected)
HIV persistence during therapy
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Short-lived infected cell
Long-lived infected cell(latently infected)
HIV persistence during therapy
Antiretroviral therapy
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Short-lived infected cell
Long-lived infected cell(latently infected)
HIV persistence during therapy
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Lerner et al. J Virology 2011: Patient undergoing STI
Alexander et al. JAIDS 2003 Patient undergoing multiple STI
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Untreated HIV infection
Short-lived infected cell
Long-lived infected cell(latently infected)
Virus particle
Non-infected cell
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Untreated HIV infection
Short-lived infected cell
Long-lived infected cell(latently infected)
Virus particle
Non-infected cell
Treated with optimal antiretroviral therapy
Prevents disease progression but no cure (rare infected cells persist)
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Untreated HIV infection
Short-lived infected cell
Long-lived infected cell(latently infected)
Virus particle
Non-infected cell
Treated with optimal antiretroviral therapy
Prevents disease progression but no cure (rare infected cells persist)
•Latently infected CD4+ T lymphocytes are rare in vivo:
•Approximately 1 per 106 total resting CD4+ T cells
•Probably constitute around 105-106 cells per patient
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Marsden & Zack: Bioorg Med Chem Lett. 2013 Jul 15;23(14):4003-10.
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Marsden & Zack, Bioorg Med Chem Lett. 2013
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Rose Bowl Capacity = 92,542
Approximately 1 per million resting CD4+ T cells harbor a latent provirus.
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Rose Bowl Capacity = 92,542
Approximately 1 per million resting CD4+ T cells harbor a latent provirus.
To cure the infection we need to do this with 1,000,000 (one million) cells hidden in this way.
Like finding one person in 11 football stadiums.
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Treated with optimal antiretroviral therapy
Short-lived infected cell
Long-lived infected cell(latently infected)
Virus particle
Non-infected cell
HIV-resistant cells
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Treated with optimal antiretroviral therapy
Ablative therapy (destroys immune system)Followed by transplant with HIV-resistant cells
Short-lived infected cell
Long-lived infected cell(latently infected)
Virus particle
Non-infected cell
HIV-resistant cells
Might allow cure of infection (elimination of all replication-competent virus)
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Treated with optimal antiretroviral therapy
Ablative therapy (destroys immune system)
X
Followed by transplant with HIV-resistant cells
Short-lived infected cell
Long-lived infected cell(latently infected)
Virus particle
Non-infected cell
HIV-resistant cells
Might allow cure of infection (elimination of all replication-competent virus)
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http://pozmagazine.tumblr.com/post/5137593713/timothy-brown-a-k-a-the-berlin-patient-is-the
The “Berlin Patient”
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http://www.thefullwiki.org/Discovery_and_development_of_CCR5_receptor_antagonists
HIV enters cells by binding to CD4 and a “corecepter” (often CCR5).
CCR5 is not functional in approximately 1% of Caucasians, which means they are highly resistant (but not completely immune) to infection with most strains of HIV.
This mutation is called CCR532.
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• The “Berlin Patient” was HIV positive and also developed leukemia.
• He underwent aggressive chemotherapy to clear the leukemia, and in the process almost all the HIV+ cells in his body were also killed.
• This patient then received two bone marrow transplants from a CCR5-32 individual.
• The new immune cells were not susceptible HIV, and the virus in currently undetectable more than seven years post-transplant.
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Modified from : http://www.cancer.gov/cancertopics/understandingcancer/immunesystem
Cells of the Immune System
Multipotentialstem cell
Hematopoieticstem cell
Platelets
Macrophage
ErythrocytesEosinophil
Neutrophil
Megakaryocyte
Mast cell
Basophil
T lymphocyte
Natural killer cell
Dendritic cell
B lymphocyte
Lymphoid progenitor cell
Myeloid progenitor
cell
Monocyte
Marrow
Bone
CD4+ T cell
CD8+ T cell
Marrow
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Modified from : http://www.cancer.gov/cancertopics/understandingcancer/immunesystem
Cells of the Immune System
Multipotentialstem cell
Hematopoieticstem cell
Platelets
Macrophage
ErythrocytesEosinophil
Neutrophil
Megakaryocyte
Mast cell
Basophil
T lymphocyte
Natural killer cell
Dendritic cell
B lymphocyte
Lymphoid progenitor cell
Myeloid progenitor
cell
Monocyte
Marrow
Bone
CD4+ T cell
CD8+ T cell
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Modified from : http://www.cancer.gov/cancertopics/understandingcancer/immunesystem
Cells of the Immune System
Multipotentialstem cell
Hematopoieticstem cell
Platelets
Macrophage
ErythrocytesEosinophil
Neutrophil
Megakaryocyte
Mast cell
Basophil
T lymphocyte
Natural killer cell
Dendritic cell
B lymphocyte
Lymphoid progenitor cell
Myeloid progenitor
cell
Monocyte
Marrow
Bone
CD4+ T cell
CD8+ T cell
![Page 24: HIV Cure Research Updates Dr. Matthew Marsden Adj. Assistant Professor, UCLA Department of Medicine 9/3/14.](https://reader030.fdocuments.net/reader030/viewer/2022033103/56649d705503460f94a52ba4/html5/thumbnails/24.jpg)
Modified from : http://www.cancer.gov/cancertopics/understandingcancer/immunesystem
Cells of the Immune System
Multipotentialstem cell
Hematopoieticstem cell
Platelets
Macrophage
ErythrocytesEosinophil
Neutrophil
Megakaryocyte
Mast cell
Basophil
T lymphocyte
Natural killer cell
Dendritic cell
B lymphocyte
Lymphoid progenitor cell
Myeloid progenitor
cell
Monocyte
Marrow
Bone
CD4+ T cell
CD8+ T cell
![Page 25: HIV Cure Research Updates Dr. Matthew Marsden Adj. Assistant Professor, UCLA Department of Medicine 9/3/14.](https://reader030.fdocuments.net/reader030/viewer/2022033103/56649d705503460f94a52ba4/html5/thumbnails/25.jpg)
Modified from : http://www.cancer.gov/cancertopics/understandingcancer/immunesystem
Cells of the Immune System
Multipotentialstem cell
Hematopoieticstem cell
Platelets
Macrophage
ErythrocytesEosinophil
Neutrophil
Megakaryocyte
Mast cell
Basophil
T lymphocyte
Natural killer cell
Dendritic cell
B lymphocyte
Lymphoid progenitor cell
Myeloid progenitor
cell
Monocyte
Marrow
Bone
CD4+ T cell
CD8+ T cell
CCR5-32
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Figure 1. Timeline for clinical treatments and study samples.
Yukl SA, Boritz E, Busch M, Bentsen C, et al. (2013) Challenges in Detecting HIV Persistence during Potentially Curative Interventions: A Study of the Berlin Patient. PLoS Pathog 9(5): e1003347. doi:10.1371/journal.ppat.1003347http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003347
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Table 4. Summary of virologic measures.
Yukl SA, Boritz E, Busch M, Bentsen C, et al. (2013) Challenges in Detecting HIV Persistence during Potentially Curative Interventions: A Study of the Berlin Patient. PLoS Pathog 9(5): e1003347. doi:10.1371/journal.ppat.1003347http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003347
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Why can’t we use this approach for everybody?
•The chemotherapy and bone marrow transplant procedure was very risky (the patient nearly died).
•Matching donors that are also CCR5-32 are very hard to find.
•The procedure is very expensive, time consuming, and requires excellent medical facilities (not feasible in many parts of the world) .
•The patient will have to take immunosuppressive drugs for the rest of their life to avoid problems with the transplant (this may be worse than just taking the anti-HIV drugs).
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The “Boston Patients”
Dr. Timothy Henrich of Brigham and Women's Hospital
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http://www.cnn.com/2013/12/07/health/hiv-patients/
Bone marrow transplant with unprotected (not HIV-resistant) donor cells “the 2 Boston Patients” delayed viral rebound…..
But did not prevent it...
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• The “Boston Patients” were HIV positive and also developed leukemia.
• They underwent reduced-intensity chemotherapy to clear the leukemia (stayed on antiretroviral therapy during this process).
• They then received a bone marrow transplants (not HIV-resistant cells).
• Stayed on ART for 2.6 and 4.3 years and virus was not detectable.
• Upon treatment interruption, viral rebound occurred after 3 and 8 months.
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Treated with optimal antiretroviral therapy
Short-lived infected cell
Long-lived infected cell(latently infected)
Virus particle
Non-infected cell
HIV-resistant cells
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Treated with optimal antiretroviral therapy
Followed by transplant with non-HIV resistant cells
Short-lived infected cell
Long-lived infected cell(latently infected)
Virus particle
Non-infected cell
HIV-resistant cells
Delayed virus rebound after stopping therapy but did not prevent it
Conditioning therapy (destroys most immune cells)
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The “Mississippi baby”
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“An infant was born by spontaneous vaginal delivery at 35 weeks of gestation to a woman who had received no prenatal care. Rapid HIV-1 testing in the mother was positive during labor. Delivery occurred before antiretroviral prophylaxis was administered. Maternal HIV-1 infection was confirmed by means of Western blot testing.”
Detection of Human Immunodeficiency Virus Type 1 (HIV-1) Infection in the Child.
Persaud D et al. N Engl J Med 2013;369:1828-1835.
http://www.nejm.org/doi/full/10.1056/NEJMoa1302976#t=article
“ART was initiated in the infant at 30 hours of age. A three-drug regimen of zidovudine (at a dose of 2 mg per kilogram of body weight every 6 hours), lamivudine (at a dose of 4 mg per kilogram twice daily), and nevirapine (at a dose of 2 mg per kilogram twice daily) was selected to provide prophylaxis for high-risk HIV-1 exposure and to minimize the likelihood of generating resistant viral variants in the event that the infant had been infected in utero.”
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Detection of Human Immunodeficiency Virus Type 1 (HIV-1) Infection in the Child.
Persaud D et al. N Engl J Med 2013;369:1828-1835.
http://www.nejm.org/doi/full/10.1056/NEJMoa1302976#t=article
Solid arrow = Last prescription for ART filledDashed arrow = Time of last ART administration
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http://www.usatoday.com/story/news/nation/2014/03/05/hiv-baby-cure/6081221/
The “LA Baby” has a similar story to the “Mississippi baby”, but has yet to undergo ART treatment interruption.
“The girl was delivered at Miller Children's Hospital in Long Beach, California, last summer to a mother with HIV who had not received antiretroviral drugs during pregnancy. Doctors gave the baby high doses of three drugs -- AZT, 3TC and Nevirapine -- four hours after birth. Eleven days later, the virus was undetectable in her body and remained undetectable eight months later.”http://www.cnn.com/2014/03/06/health/hiv-baby-cured/
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Untreated HIV infection in newborn- Limited reservoir cells?
Short-lived infected cell
Long-lived infected cell(latently infected)
Virus particle
Non-infected cell
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Untreated HIV infection in newborn- Limited reservoir cells?
Short-lived infected cell
Long-lived infected cell(latently infected)
Virus particle
Non-infected cell
Early treatment with potent antiretroviral therapy
Still under investigation- Perhaps the early treatment reduced latent reservoir size
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The “VISCONTI cohort”
Viro-Immunologic Sustained COntrol after Treatment Interruption
“Functional cure” for some patients?
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“we have observed that some HIV-infected patients interrupting a prolonged antiretroviral therapy initiated close to primary infection are able to control viremia afterwards. We present here 14 of such post-treatment controllers.”
“Finally, we estimated the probability of maintaining viral control at 24 months post-early treatment interruption to be ~15%, which is much higher than the one expected for spontaneous control.”
Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, et al. (2013) Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study. PLoS Pathog 9(3): e1003211. doi:10.1371/journal.ppat.1003211http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003211
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Table 1. Characteristics of PTC included in the study.
Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, et al. (2013) Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study. PLoS Pathog 9(3): e1003211. doi:10.1371/journal.ppat.1003211http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003211
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The immune response during acute HIV-1 infection: clues for vaccine developmentAndrew J. McMichael, Persephone Borrow, Georgia D. Tomaras, Nilu Goonetilleke & Barton F. HaynesNature Reviews Immunology 10, 11-23 (January 2010)
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Figure 1. Long-term control of viremia and stable CD4+ T cell counts in fourteen patients after interruption of antiretroviral treatment initiated in primary HIV-1 infection.
Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, et al. (2013) Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study. PLoS Pathog 9(3): e1003211. doi:10.1371/journal.ppat.1003211http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003211
Grey Shading = Periods where patients received therapy
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New experimental gene therapy/transplantation cure approaches
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Marsden & Zack, Bioorg Med Chem Lett. 2013
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Treated with optimal antiretroviral therapy
Followed by transplant with HIV-resistant cells
Short-lived infected cell
Long-lived infected cell(latently infected)
Virus particle
Non-infected cell
HIV-resistant cells
Might prevent disease progression or create “functional cure” (some virus still present but contained without drugs)
Conditioning therapy (destroys most immune cells)
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Experimental activation-elimination approaches to deplete latent HIV
“Kick and Kill”
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Marsden MD, Zack JA. Future Virol. 2010 Jan 1;5(1):97-109.
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Activation of latent provirus expression
A) Induce latently-infected cell to produce viral proteins
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B) Kill resultant productively-infected cell
Marsden & Zack, Bioorg Med Chem Lett. 2013
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http://boingboing.net/2009/08/30/how-science-reportin.html
Headlines often don’t tell the full story!
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Take-home points:
• HIV cure research is a major focus of the scientific community and governmental funding agencies.
• It is hard to definitively prove that a person is cured of HIV because virus may emerge from rare infected cells many years after stopping therapy.
• However, there is a single case in which HIV might have been cured (Berlin Patient).
• The circumstances of this cure is highly unusual (ablative therapy, GVHD, and bone marrow transplant with resistant cells), and therefore cannot be directly applied to all infected people.
• Important as proof of concept for HIV cure.
• More studies are being performed to develop new cure approaches that can be more widely used.
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Thank You!
Questions?