CCR5 Gene Therapy to Cure HIV? Many expectations, few answers PDF Print E-mail
Written by Alain Lafeuillade   
Thursday, 22 September 2011 10:19

CCR5 Gene Therapy to Cure HIV? Many expectations, few answers

gene-therapy

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  

We need a cure that is scalable, deliverable, and cheap

Obviously gene therapy with ZFN does not fulfil these requirements.

 

Without saying like her that  

Gene therapy is scientifically flawed and [at] high risk

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.

 

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.

 

References

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
Last Updated on Thursday, 22 September 2011 11:20
 

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David Margolis 23.09.2011 (01:31:55)  
CCR5 Gene Therapy to Cure HIV? Many expectations, few answers Yes No  

I agree with you, overall, Alain. we should recognize what is good here, though:
1) safety short-term. Although we will have to watch to see if nicking the gene at CCR5 rarely nicks other genes and leads to cancers (a la prior experience with retroviral gene therapy)
2) the ability to edit a human gene: this might benefit human genetic diseases, especially where less than 100% repair resolves the disease phenotype.
We can hope for:
>>increased scalability over time: ART was supposed to be un-doable in Africa, once.
>>that these modified T cells have immune function and are not exhausted by ex vivo expansion

 
   
       
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Malcolm Macartney 25.09.2011 (15:01:11)  
CCR5 Gene Therapy to Cure HIV? Many expectations, few answers Yes No  

Could not agree with this more. So many studies are published to great acclaim but without the scientific back-up. This area is one of great potential and these results highlight where our knowledge and expertise is deficient. At this point in time, this has great potential but needs lots more work.

 
   
       
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deo 02.05.2012 (16:47:07)  
CCR5 Gene Therapy to Cure HIV. Yes No  

Dismissing gene therapy is wrong. I genuinely believe gene therapy is the only way forward in dealing with HIV. Here are my reasons:
1. For over 30 years our results we have failed to come up with a cure. Infact no cure is in site.
2. The most effective arvs are basically enzyme inhibitors. These drugs have made a HUGE difference in the lifes of our patients living with HIV but they have many side effects, are hard to take, etc and worse the virus soon becomes resistant by mutating.
3. People have to have hope. A life without hope is not a life at all.
4. There is published evidence that people with certain genes (specifically ccr5 delta 32 mutation) are more resistant to hiv. This is really cool but we should try to get this "mutation" into more patients. Our first role as doctors is to save life and the rest come later.
5. Gene therapy is not perfect but i believe in my heart that it should be our focus.

 
   
       

Smileys

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