HIV Reservoirs Part 6: Gene Therapy

HIV persists in treated individuals by the establishment of latency and long term reservoirs. It is known that a deletion on the CCR5 coreceptor gene can provide some kind of resistance to HIV. Therapeutic attempts to mimic this situation are promising.

HIV "resistance"

Several genetic factors are linked to a slower disease progression or to resistance at acquiring HIV. For example, some markers of the HLA system (HLA B27, HLA B57) are associated with a slower progression in already infected individuals.

To infect a cell, HIV needs a receptor, the CD4 receptor, and a co-receptor, CCR5 or CXCR4. Patients who present a delta 32 deletion on the gene coding for CCR5 are relatively resistant to HIV infection.

Proof of Concept: the Berlin patient

An HIV infected patient from Berlin has been reported mid 2009 for a possible cure of HIV infection following 2 bone marrow transplants. This cure was confirmed in another report in December 2010.

In fact, this patient presented acute leukemia, and this diagnosis was the initial reason for the bone marrow transplant. Because of a leukemia relapse, the transplant was done twice.

The particularity was in the choice of the bone marrow donor: a donor chosen according to his HLA compatibility, but also bearing the delta 32 CCR5 deletion!

Antiretroviral therapy was stopped in this patient and both HIV RNA and DNA remain undetectable after nearly 4 years of follow up.

From Man to Mice back to Men

This case prompted the research community to set up experiments in mice. In this model, stem cells modified by a Zinc Finger Nuclease were used. The Zinc Finger Nuclease acts like a molecular scissor, able to delete the gene coding for CCR5. After engrafting infected mice, the "protected" cell population was shown to expand and proliferate.

These encouraging results led to an ongoing experiment in humans. CD4 T cells from patients were collected, treated with the Zinc Finger Nuclease, then re-infused. The preliminary results presented in recent meetings show that these modified T cells, resistant to HIV, persist and expand in the host.

Consequently, this approach could be a way to 'sabotage' HIV infection, allowing an intact immune system to grow despite persistent ongoing infection.

Alain Lafeuillade, MD, PhD
http://www.hiv-eradication.org

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HIV Functional Cure Getting Closer With Gene Therapy?

Through the wonders of gene therapy, the world is just that much closer to finding a functional cure for HIV. A functional cure is one such that HIV within the body is reduced to undetectable levels without antiretroviral therapy and so low that the body's own natural immune system can keep it in check. In order to reach that, technological and medical advances had to be made. Those advances just produced breakthrough results. Researchers at Sangamo BioSciences in Richmond, California, recently conducted a trial with a new type of gene therapy that reduced levels of the virus and, in the case of one patient, led to undetectable viremia.

The firm has announced that it has found a way to enrich the T-cells that fight HIV within the body and protect them from being infected by HIV themselves through gene therapy. Using zinc finger nucleases, the T-cells are transformed to get a mutation on the CCR5 co-receptor. This co-receptor is one that allows HIV to infect cells, but a disruption in the gene makes the cell resistant to HIV infection. In effect, it mimics the same result naturally found in the small percentage of humans who are born with this genetic mutation. This is the same mutation that cured the "Berlin Patient" of HIV through bone marrow transplant last December.

Researchers decided on this approach after realizing that some people actually do have natural protection against HIV. Humans typically have two copies of every gene. Well, if a person has mutations in both CCR5 genes, it renders them protected against most HIV strains. If a person holds only one of the two genes mutated, HIV infection is possible, but the disease progression is slower than usually. This aforementioned mutation is only found in less than 1 percent of the world's population-mostly of European descent-and may have been an evolutionary response to protect against the Black Death plague of the 14th century that wiped out well over half of Europe's population.

An estimated 33 million people worldwide have HIV, and this could be the start of finding a cure for those people. Replicating the genetic mutation in this small pool of individuals wasn't even thought of until the serendipitous HIV cure of the Berlin Patient, but researchers are pleased that such an event occurred to shine a light on this important subject. The path toward an HIV cure continues to grow shorter, and that's encouraging to the many millions of people who live with HIV.

International Symposium on HIV & Emerging Infectious Diseases (ISHEID): the world leading AIDS experts will gather for the 2012 HIV AIDS ISHEID conference in Marseille, France, May 23-25, 2012. The general AIDS conference theme will be 'From Universal HIV Testing to HIV Cure'.

http://www.isheid.com

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HIV Cure: Gene Therapy Results Still Preliminary

HIV experts are optimistic about a recent study in which researchers were able to reconfigure blood cells, making them resistant to HIV. This trial was done on six HIV infected patients successfully treated with antiretroviral therapy (ART). But experts are not sure yet if this will actually be a cure to the deadly disease, though they all agree it is a step in the right direction. This study was done after a man in Berlin received a stem cell transplant and four years later is cured from HIV.

The HIV gene therapy results were announced in March 2011 during a medical conference in Boston, Massachusetts. This is a positive sign that there might be a cure found in the near future and will generate excitement in researchers to keep looking. This new approach will not completely eliminate HIV from the body, but it will make the virus controllable, most likely without the need of medication. It is called a functional cure.

An autologous cell transplant was performed in the study, where a human gene was permanently deleted and the altered cells were infused back into the patient. Previous gene therapies were to muffle the activity of a gene or add a new gene, both approaches where unsuccessful. Specifically, six men with HIV had some blood filtered and some T-Cells removed from that blood. A gene-snipping compound called 'zinc finger nuclease' was added to the T-cells. The modified cells were then mixed with growth factors before infusing them back into the patient's blood stream. Half of the men received about five billion modified cells and the other half received about 205 billion modified cells. After a year, these modified cells are still thriving and multiplying.

HIV attacks a person's T-cells, which are special immune system cells, through a protein receptor called CD4 and a coreceptor called CCR5. There are some people that lack the CCR5 gene and are naturally immune to HIV. When a person lacking the CCR5 gene donated bone marrow to a person with leukemia, who also happened to be HIV positive, the HIV infection was cured. This sparked the study. The patients had about two days worth of flu-like symptoms, which was the only reported side effect during the study. Not only is this a huge step in finding a cure for HIV and AIDS, but it is a huge revelation in the field of genetics. It is the first time in the history that doctors succeed to achieve a sabotage of the natural history of HIV infection.

The reference scientific workshop on HIV Persistence, HIV Reservoirs & Eradication Strategies: http://www.informedhorizons.com/persistence2011/

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