HIV Cure Research Updates Dr. Matthew Marsden UCLA Department of Medicine

HIV Cure Research UpdatesDr. Matthew MarsdenUCLA Department of Medicine

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

http://www.nature.com/news/french-teenager-healthy-12-years-after-ceasing-hiv-treatment-1.17951

• Why is HIV difficult to cure?

• Documented cases of apparent cures

• New gene therapy/transplant approaches

• Additional therapeutic approaches

Sterilizing cure:No replication-competent HIV present in the body.

“Functional cure”:Some replication-competent virus might be present, but it is controlled without drugs and therefore will allow for long periods of drug-free remission.

Short-lived infected cell

Long-lived infected cell(latently infected)

HIV persistence during therapy




Antiretroviral therapy




Lerner et al. J Virology 2011: Patient undergoing STI

Alexander et al. JAIDS 2003 Patient undergoing multiple STI

Untreated HIV infection



Virus particle

Non-infected cell




Virus particle

Non-infected cell

Treated with optimal antiretroviral therapy

Prevents disease progression but no cure (rare infected cells persist)




Virus particle

Non-infected cell


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

Marsden & Zack: Bioorg Med Chem Lett. 2013 Jul 15;23(14):4003-10.

Marsden & Zack, Bioorg Med Chem Lett. 2013

Rose Bowl Capacity = 92,542

Approximately 1 per million resting CD4+ T cells harbor a latent provirus.

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.




Virus particle

Non-infected cell

HIV-resistant cells


Ablative therapy (destroys immune system)Followed by transplant with HIV-resistant cells



Virus particle

Non-infected cell

HIV-resistant cells

Might allow cure of infection (elimination of all replication-competent virus)


Ablative therapy (destroys immune system)

X

Followed by transplant with HIV-resistant cells



Virus particle

Non-infected cell

HIV-resistant cells

Might allow cure of infection (elimination of all replication-competent virus)

http://pozmagazine.tumblr.com/post/5137593713/timothy-brown-a-k-a-the-berlin-patient-is-the

The “Berlin Patient”

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.

• 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.

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





Platelets

Macrophage


Neutrophil

Megakaryocyte

Mast cell

Basophil

T lymphocyte

Natural killer cell

Dendritic cell

B lymphocyte


Myeloid progenitor

cell

Monocyte

Marrow

Bone

CD4+ T cell

CD8+ T cell





Platelets

Macrophage


Neutrophil

Megakaryocyte

Mast cell

Basophil

T lymphocyte

Natural killer cell

Dendritic cell

B lymphocyte


Myeloid progenitor

cell

Monocyte

Marrow

Bone

CD4+ T cell

CD8+ T cell





Platelets

Macrophage


Neutrophil

Megakaryocyte

Mast cell

Basophil

T lymphocyte

Natural killer cell

Dendritic cell

B lymphocyte


Myeloid progenitor

cell

Monocyte

Marrow

Bone

CD4+ T cell

CD8+ T cell





Platelets

Macrophage


Neutrophil

Megakaryocyte

Mast cell

Basophil

T lymphocyte

Natural killer cell

Dendritic cell

B lymphocyte


Myeloid progenitor

cell

Monocyte

Marrow

Bone

CD4+ T cell

CD8+ T cell

CCR5-32

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

http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1003347

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


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).

N Engl J Med 2014;371:2437-2438.

Men with Human Immunodeficiency Virus Type 1 (HIV-1) Infection Who Received an Allogeneic Transplant from a

Stem-Cell Donor Who Was Homozygous for the CCR5 delta32/delta32 Mutation.

http://www.nejm.org/doi/full/10.1056/NEJMc1412279

The “Boston Patients”

Dr. Timothy Henrich of Brigham and Women's Hospital

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...

• 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.

Boston Stem Cell Transplants Revisited

Henrich TJ, et al. 21st CROI 2014, Abstract #144LBDays Post ATI

Slide from E. Daar




Virus particle

Non-infected cell

HIV-resistant cells


Followed by transplant with non-HIV resistant cells



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)

The “Mississippi baby”

“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.”

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

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/

Untreated HIV infection in newborn- Limited reservoir cells?



Virus particle

Non-infected cell

Untreated HIV infection in newborn- Limited reservoir cells?



Virus particle

Non-infected cell

Early treatment with potent antiretroviral therapy

Still under investigation- Perhaps the early treatment reduced latent reservoir size

The “VISCONTI cohort”

Viro-Immunologic Sustained COntrol after Treatment Interruption

“Functional cure” for some patients?

“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


Table 1. Characteristics of PTC included in the study.



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)

http://www.nature.com/nri/journal/v10/n1/full/nri2674.html

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.


Grey Shading = Periods where patients received therapy


“A French teenager who was infected with HIV at birth has lived in good health an astonishing 12 years since she last took antiretroviral drugs, researchers say. The case — the longest-known example of a paediatric HIV patient living without ill effect after discontinuing treatment — adds to the overwhelming body of knowledge supporting the benefits of early treatment, and will help researchers to better understand why some patients with HIV can go into remission after ceasing treatment.”

http://www.nature.com/news/french-teenager-healthy-12-years-after-ceasing-hiv-treatment-1.17951

New experimental gene therapy/transplantation cure approaches



Followed by transplant with HIV-resistant cells



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)

Experimental activation-elimination approaches to deplete latent HIV

“Kick and Kill”

Marsden MD, Zack JA. Future Virol. 2010 Jan 1;5(1):97-109.

Activation of latent provirus expression

A) Induce latently-infected cell to produce viral proteins

B) Kill resultant productively-infected cell


http://boingboing.net/2009/08/30/how-science-reportin.html

Headlines often don’t tell the full story!

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 (including functional cures) that can be more widely used.

Thank You!

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HIV Cure Research Updates Dr. Matthew Marsden UCLA Department of Medicine