Zinc Fingers and Gene Therapies for HIV: Mimicking the Cured Berlin Patient?
March 2, 2011
Jay Lalezari, M.D., from the University of California-San Francisco presented first-of-its-kind study data on the use of zinc finger nucleases (ZFNs) to artificially disrupt the CCR5 receptor on the surface of CD4 cells, which HIV uses to infect its human host. The study is an attempt to determine if genetically modifying a patient's own CD4 cells could result in the augmenting of the patient's immune system with lasting, HIV-resistant cells.
Some HIV-infected patients who have an undetectable viral load while taking HIV medications continue to have low CD4+ cell counts. Lalezari et al decided to perform their proof-of-concept study on six of these patients: Each was on HIV antiretrovirals, had an undetectable HIV viral load, had a CD4+ cell count between 200 and 500, and had been HIV infected for more than 20 years. The patients were enrolled in one of two cohorts: in one, 10 billion total cells were modified; in the other, 20 billion. The process involved autologous (i.e., derived from the patient) R5-disrupted T cells that were expanded and modified with ZFNs outside the patients' bodies and then infused into the patients. The patients were followed weekly for one month and then monthly for 11 months post-infusion; blood and rectal mucosa samples were taken.
This novel study construction is the result of a history of groundbreaking findings. CCR5 has long been of interest to HIV researchers because many people who are resistant to HIV infection have a mutation in their CCR5 gene: the delta32 mutation. A minority of people of northern European descent (1% to 2.5%) have this mutation in the CCR5 receptor. After studying these patients, the oral CCR5 inhibitor drug maraviroc (MVC, Selzentry, Celsentri) was developed and ultimately approved in the U.S. in 2007. Fears that blocking the CCR5 receptor would lead to more rapid HIV disease progression or the emergence of other health problems have slowly dissipated since the drug was first given to humans in studies. (That said, there are some known adverse effects of CCR5 receptor blocking, including increased susceptibility to West Nile virus.)
As maraviroc was being developed, companies such as Sangamo BioSciences, Inc., were already trying to block the CCR5 receptor in a more permanent way: by using zinc finger nucleases, which act like scissors that cut the gene that codes for that receptor. But in the past, studies trying to modify CD4 cells in this manner have shown limited persistence of these cells after infusion in patients.
At the same time, some clinicians around the world were also trying to think outside the box on how to block HIV entry into CD4 cells. One such progressive thinker was Gero Hütter, M.D., from the Charité-Universitätsmedizin in Berlin. He had an HIV-infected patient with leukemia; he decided to try to treat both the patient's leukemia and HIV via a stem cell transplant using a donor with the delta32 mutation.
Hütter (and his patient) was lucky to find such a donor. The transplant -- which treats leukemia by essentially rebooting the body's immune system and creating new white blood cells -- also had the benefit of wiping out the HIV infection in the patient. The results of this extraordinary case were presented at CROI 2008 without receiving much excitement from the medical community.
It wasn't until almost two years later -- when it was found that the "Berlin patient" was still free of HIV not only in the blood, but in other compartments as well -- that excitement grew. Now, four years later, the patient remains HIV-free, which suggests he is cured of the disease. This has given companies such as Sangamo even more motivation to pursue a potential functional cure via disruption of the CCR5 receptor.
The data presented by Lalezari about Sangamo's ZFN approach showed several things:
- The infusion was safe and well tolerated.
- CD4+ cell count increases were seen in five of the six patients. The patient who did not respond had pre-existing antibodies to the adenovirus vector used to deliver the ZFN into the CD4 cell, so his body destroyed the vector, rendering the ZFN inactive. About 50% of the human population has those same antibodies, so a different vector may be used in future studies.
- The percentage of CCR5 disruption in the peripheral blood of the five responders was 6%, 3%, 1%, 2%, and 2% (respectively) at day 14 and persisted for the duration of the follow-up. CD4+ cell counts increased in all patients at day 14 (from an average of 35 to 1038 cells/mm3) and were sustained at all time points (with mean increases of 208, 86, 233, 911, 210 cells/mm3, respectively). CCR5-disrupted cells were detected in the rectal mucosa of all patients at all assessed time points, with levels of CCR5 disruption approximating that of peripheral blood when normalized for CD4 cells within each compartment.
- Three of the five responders had normalization of the CD4/CD8 ratio, which is a hallmark of the health of the immune system.
- There was a good uptake (grafting) of the modified CD4 cells into the blood of the five responders. In fact, by day 14 these patients had three times the quantity of cells that had been infused, showing that there was a growth of modified cells in their bodies. By day 90, the levels of persistent engraftment had become 6- to 40-fold greater than previously reported. After three months, 6% to 7% of the CD4 cells in the circulating blood had evidence of gene modification, which is over 10-fold higher than achieved by any previous T-cell modification therapy in HIV.
- Homing of these cells to the gut mucosa was observed in all patients tested, with CCR5 disruption levels similar to that of peripheral blood, suggesting these cells traffic normally. This is important since gut mucosa is the interface between the immune system and HIV.
- As I noted above, there were two cohorts in dosing: 10 and 20 billion cells. There seemed not to be a response difference between those two cell doses. Cells grafted and expanded during the first two weeks.
This exciting study opens the door to new possibilities, but many questions remain unanswered:
- What will happen long-term with the newly engrafted CD4 cells? Will they provide a survival or comorbidity benefit in these patients? (Note: Patients in this study will be followed for life.)
- Will this approach help control HIV replication in patients who stop antiretrovirals after long-term HIV suppression? How can we ethically ask patients to enroll in studies that require a structured treatment interruption? Will institutional review boards be willing to approve these kinds of studies in the future?
- Do people do better with more than one infusion? What is the best number of cells to ensure optimum immunological response?
- Will this approach help control HIV replication in treatment-naive patients who have a detectable viral load and who are not taking HIV antiretrovirals? Will these cells still have a survival advantage when challenged with untreated HIV? (Note: Lalezari is currently enrolling a 14-patient study in San Francisco that will attempt to answer these questions.)
- Will these gene-modified cells have a survival and activity advantage against HIV across the board? Will HIV viral load be controlled well enough for people to stop using antiretrovirals -- or, as stated in the question above, allow them to avoid antiretrovirals entirely?
- What will the cost of this procedure be?
- What happens to those with pre-exposure to the adenovirus vector who cannot respond to this type of zinc finger nuclease delivery method?
We should be careful not to overreach with these data. Many people are throwing the "cure" word around when talking about this study, but this is just a very preliminary effort to start answering important questions toward that goal.
At a CROI 2011 press conference, Lalezari and other researchers involved in zinc finger nuclease and HIV gene therapy research discussed their findings and the broader implications of those findings. Click here to read that transcript.
Copyright © 2011 The HealthCentral Network, Inc. All rights reserved.
This article was provided by TheBodyPRO.com. It is a part of the publication The 18th Conference on Retroviruses and Opportunistic Infections
Comment by: Ed
Wed., Dec. 14, 2011 at 4:58 pm EST
Does anyone have any updates regarding this trial?
Maybe the volunteers of the trial can comment?
Would be much appreciated. I've only been positive 1 year but I share the hope and cautious optimism of this new treatment.
Comment by: Singer44
Sat., Mar. 19, 2011 at 8:44 am EDT
Fascinating reading- the followup results being reported on is remarkable. Ive been in several studies involving interruption of treatment; each successive study I was able to stay longer before any rebound. The third dry spell was the longest; rebound after a year was less than 100, and it stayed that low until the doctor put me back on a low-dose medication regimin. My T cells were (and still are) 1000 or more.
As long as there are willing volunteers we will make progress and its essential for people to continue to offer themselves as living laboratories in the fight against this disease.
Comment by: Michael
Thu., Mar. 10, 2011 at 4:23 pm EST
This is absolutely amazing!!! We want this out of the labs and into the offices of HIV doctors ASAP!!!!
Comment by: Crispy Fried Toad
Wed., Mar. 9, 2011 at 6:53 pm EST
hello. i'm praying for a cure for this condition... and to thank God for all those gay men that took part in medical trials over the years to get this far down the road to the cure.
Comment by: kelly
Sun., Mar. 6, 2011 at 1:55 am EST
great news for the research model,Having survived with it for 15 years and living a healthy lifestle has been my only hope til now. I look forward to being around to take the cure into my system,keep up the good work!
Comment by: Tommy
Sat., Mar. 5, 2011 at 9:58 am EST
Hey Guys the cure should have been here a long time ago, its the govement that does not want a cure for hiv... the govement makes so much money off hiv treatment,
l wish the govement would stop putting the breaks on research like this !!! lets be honest if the govement could make money on a cure for hiv, l bet it would have beeh here already.... but l think reseachers are knocking that hard and getting so close... not even the govement can stop them.... c,mon lets change 34 million lives who have hiv and the other 4 million who have it but don't know they have it....
Replies to this comment:
Comment by: David
Tue., Mar. 8, 2011 at 2:42 pm EST
I don't believe it's the government who is standing in the way of progress. I think it is the pharma companies themselves. They are out to make money, and there is no money in a cure. They can make much, much more money by producing drugs that you have to take for your entire life. They make no money after you are cured. So there is no incentive for them to find a cure. At least, this is the case in the United States. In other countries with universal health care, there IS an incentive to cure people, because there would be less of a drain on the national healthcare funds. So it is the American system (and the pharma companies) that are working against us. That's why the healthcare industry was so opposed to Obama's national healthcare idea. They knew they would make less money. They want to keep the system as it is now: expensive, complicated, and fickle.
Comment by: Dave
Wed., Mar. 9, 2011 at 3:49 pm EST
Sorry, but I disagree. While I would guess that there is a longer life to the "cash cow" for meds, I believe that the technologies that might produce a functiona cure will garner huge amounts of money as well. Further, what ever the technology is behind the "functional cure" there will be competetion to land a patent for an "actual cure." Just maybe this technology will have other applications for other diseases as well. God please let this be the beginning of a cure. We have all suffered far too long and have lost far too many people! Peace.
Comment by: ethanw.
Sat., Mar. 19, 2011 at 5:59 pm EDT
Well, i guess the conspiracy theories will never die. Ugh. The reason we haven't found a cure is because of the expense of doing trials on human beings. Also because we have lost faith and the hiv/aids epidemic has been around for so long,we have learned to ignored it. There has been incredible progress by some very talented researchers (Jay Lelazari and Paula Cannon, to name two) but they need money and interest to research in humans. If we continue with this conspiracyspeak, the cure will never come.
Comment by: Paul
Fri., Mar. 4, 2011 at 10:01 pm EST
Regarding questions 4 and 5: I am patient #1 of the 14. They've been growing my cells since February, and I'll get reinfused in May. So that's when the data will start trickling in for patients off meds.
Replies to this comment:
Comment by: Johnathan
Mon., Mar. 7, 2011 at 9:17 pm EST
I wish you the best of luck and pray that this is what our community has been waiting for so so long. My prayers go out to you and those in the study
Comment by: Dave
Wed., Mar. 9, 2011 at 3:51 pm EST
Paul, thanks for your bravery! We are all in the same boat, more or less. Please keep us informed in this exciting treatment. May God help us all; bless these scientists!!!!!
Comment by: Peter
Sat., Mar. 12, 2011 at 6:00 am EST
Jonathan, can we cut with the praying, please. This breakthrough has absolutely nothing to do with any supernatural beings or any Gods, and everything to do with responsible and determined human-beings, i.e. the scientists, the guys and gals in white coats beavering away in laboratories.
Comment by: jess
Fri., Jan. 25, 2013 at 8:17 pm EST
hi paul - how are you doing? any updates on your treatment?
Comment by: BW
(Salt Lake City)
Fri., Mar. 4, 2011 at 9:51 am EST
Diagnosed in July (10) this is stirring news I am on Atripla with a CD4 count in the low 400ís and undetectable viral load. Having read about people who had a natural resistant to HIV for many years it seemed only logical they could provide some insight into eradicating this virus. I will continue to live life to the fullest with renewed expectations to the future. I pray for the researchers and positive participants you are our future.
Comment by: Costas
Fri., Mar. 4, 2011 at 7:06 am EST
Nelson, thank you very much indeed for so elegantly, rationally, and objectively reporting this most intriguing research. It is exciting news indeed. And while it excites all of us who have been infected by HIV, it is most surely also exciting researchers worldwide who may now see a way through what has previously been a very dark maze. There is now a glimmer of light at the end of the tunnerl. Thanks for so excellently reporting this news.
Comment by: Tad
Fri., Mar. 4, 2011 at 1:35 am EST
Thank God for this progress! We have been waiting SO long. I pray this does develop into a cure.
Hang in there everyone :)
Replies to this comment:
Comment by: Stephanie Tanner
Tue., Mar. 8, 2011 at 11:33 am EST
Oh, you mean the same God conservative religious americans praised when AIDS raged the gay community in the 80s?
Comment by: Dave
Wed., Mar. 9, 2011 at 3:54 pm EST
Stephanie, It is the religious conservatives that take license with Gods love; they use God to be devisive. Since it is a matter of faith, I would like to believe that God is merciful and not hateful as some zealots would like us to believe and purport to now as fact.
Comment by: greg r
Thu., Mar. 10, 2011 at 5:54 pm EST
Well Stephanie--it's the same God that I gave thanks to 'that anti-virals 'were available to help combat this disease's progression.and continue to pray to, so that we may find a cure. You know everyplace on earth has it's idiots--it's uneducated knuckle-dragging population---time changes values and mores; but God's love for all doe,s not--it is forever lasting--no matter what culture you fall into!
Comment by: greg r
Thu., Mar. 3, 2011 at 9:12 pm EST
What very good news--after 22 years of dealing with this virus, hope has returned that wiping it out may be in the not so distant future.Maybe A cure will happen before I die of old age.....
Comment by: Jeff
(Grand Rapids, MI)
Thu., Mar. 3, 2011 at 5:19 pm EST
This is exciting news. I used to say to friends and family in a few years I think the doctors will infect me with a modified virus that will turn on the hiv and I'll be cured after a few treatments. :) I look forward to hearing about future tests and look forward as we all do, to the day we can be cured!
Comment by: Chris
(Eastern sea board)
Thu., Mar. 3, 2011 at 4:52 pm EST
I have been living with HIV for 10 years, A mere drop in the bucket compared to most. I am happy to see that we are making such progress twords a cure. Lets first see what happens to the test subjects before we all line up to be free of one problem only to be mutated into another problem.
Comment by: Coryjean
Thu., Mar. 3, 2011 at 4:46 pm EST
Very exciting to see such results! I hope the success continues and we can learn even more.
Comment by: Saad
Thu., Mar. 3, 2011 at 10:44 am EST
It's a blessing to have survived to this day in age where we are stating to hear and read about the most coveted news. I have every confidence that we are getting closer to the day of victory. The victory that will bring us all a relief to our long endured suffering and happiness we all dreamed and prayered for. So let us all celebrate at this phenomenal advancement and the new hope! I am grateful and salute to the medical advancement. God bless us all !!!
Comment by: michael
Thu., Mar. 3, 2011 at 6:38 am EST
this should be bumped up more. these are very, very exciting preliminary results.
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