CCR5 Gene Therapy to Cure HIV? Many expectations, few answers
Following the recent presentation at the 51st ICAAC of an update of ongoing trials using Zinc Finger Nucleases (ZFN) in HIV-infected patients, the company developing this therapy claims in a Press Release that “significant progress [has been made] towards a ‘functional cure' for HIV/AIDS". What are the facts?
Preliminary results of 2 phase I studies using ZFN to knock out CCR5 expression were presented at the CROI earlier this year (1, 2, and on this site). In these studies, CD4+ T cells taken from HIV-infected patients were transformed in vitro, expanded, and re-infused to patients. The CROI data showed that the procedure was well tolerated and allowed engraftment of the transformed CD4s, in particular in the gut.
Data shown at the last ICAAC (3) concerned a period of ART interruption performed in the second cohort followed in Pennsylvania. Six subjects who entered the clinical trial with CD4+ T cells of more than 450/mm3, underwent a 12 week ART interruption 4 weeks after a single infusion of transformed CD4s. The authors observed:
-a significant relation between viral load and the percentage of circulating CD4+ T cells that have undergone a biallelic modification of the CCR5 gene,
-a rebound in viremia followed by a spontaneous decrease reaching undetectable levels in 1 patient. This subject entered the study with already one CCR5 delta 32 mutation and the ZFN treatment allowed him to get biallelic transformation twice that of other subjects.
Although these results are certainly a step forward, they bring more questions than certainties.
The definition of a "functional HIV cure" means:
-undetectable viremia without ART;
-no disease progression;
-no CD4 loss;
-lack of HIV transmission.
Currently, only one patient in the ZFN trials became undetectable with a short follow up. It is totally unknown whether repeated courses of treatment will allow more patients to reach this status, and what the overall success rate would be.
With current data, telling that gene therapy with ZFN is the way towards an HIV functional cure is premature.
HIV persistence in ART-treated patients is not only a problem of persistence in CD4+ T cells but a problem of persistent inflammation, which is a driven force in the occurrence of premature aging, cancers, cardio-vascular complications. Even some "Elite Controllers maintain persistent inflammation and develop the above mentioned.
What can gene therapy do at this level is unknown.
HIV persistence involves other reservoirs than CD4+ T cells; what the fate of these other cells will be during ZFN therapy remains also unknown.
HIV has always demonstrated in the past the capacity to mutate and find ways to escape immune responses or antiretroviral therapy. What will be its ability to switch to a CXCR4 tropic strain under the pressure of ZFN-modified cells is also totally unknown.
As stated during the last IAS conference (AIDS Bacon, and on this site) by Sharon Lewin
Obviously gene therapy with ZFN does not fulfil these requirements.
We need a cure that is scalable, deliverable, and cheap
Without saying like her that
it is certainly too early to make the promise of a functional cure based on a handful of data involving few patients in a phase I trial.
Gene therapy is scientifically flawed and [at] high risk
In the past, we have sometimes induced false hope among our patients with preliminary results. The way towards a real HIV cure, either functional or sterilizing will be difficult: we cannot let them think that it is just at the corner.
1-Lalezari J, Mitsuyasu R, Deeks S, et al. Successful and persistent engraftment of ZFN-M-R5-D autologous CD4 T Cells (SB-728-T) in aviremic HIV-infected subjects on HAART. In: Program and abstracts from the 18th Conference on Retroviruses and Opportunistic Infection; February 27-March 2, 2011; Boston, MA. Abstract 46.
2- Tebas P, Levine B, Binder G, et al. Disruption of CCR5 in zinc finger nuclease-treated CD4 T cells: phase I trials. In: Program and abstracts from the 18th Conference on Retroviruses and Opportunistic Infection; February 27-March 2, 2011; Boston, MA. Abstract 165.
3-Ando D et al. HAART Treatment Interruption following Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4 T-cells (SB-728-T) to HIV-infected Subjects Demonstrates Durable Engraftment and Suppression of Viral Load. Presented at the 51st ICAAC, Chicago, 17-20 September 2011, abstract H2-794a
Key words: CCR5, CCR5 knock out, SB-728-T, functional hiv cure, hiv cure, hiv gene therapy, zinc finger nucleases