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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