POZ Community Forums
Meds, Mind, Body & Benefits => Research News & Studies => Topic started by: Tadeys on April 13, 2012, 09:40:54 am
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In a major breakthrough in the fight against AIDS, scientists claim to have for the first time shown that human stem cells can be genetically engineered to seek out and kill HIV-infected cells in a living organism.
The study demonstrates for the first time that engineering stem cells to form immune cells that target HIV is effective in suppressing the virus in living tissues in an animal model, said lead scientist Scott G Kitchen.
He added: “We believe that this study lays the groundwork for the potential use of this type of an approach in combating HIV infection in infected individuals, in hopes of eradicating the virus from the body.”
In their previous research, the scientists took CD8 cytotoxic T lymphocytes — the “killer” T cells that help fight infection — from an HIV-infected individual and identified the molecule known as the T cell receptor, which guides T cell in recognising and killing HIV-infected cells.
In their latest research, the scientists at California University similarly engineered human blood stem cells and found that they can form mature T cells that can attack HIV in tissues where the virus resides and replicates.
They did so by using a surrogate model, the humanised mouse, in which HIV infection closely resembles the disease and its progression in humans.
In a series of tests on the mice’s peripheral blood, plasma and organs conducted two weeks and six weeks after introducing the engineered cells, the scientists found that the number of CD4 “helper” T cells — which become depleted as a result of HIV infection — increased, while levels of HIV in the blood decreased.
CD4 cells are white blood cells that are an important component of immune system, helping to fight off infections.
These results indicated that the engineered cells were capable of developing and migrating to the organs to fight infection there, the PLoS Pathogens journal reported.
“We believe that this is the first step in developing a more aggressive approach in correcting the defects in the human T cell responses that allow HIV to persist in infected people,” Mr. Kitchen said.
http://www.thehindu.com/health/medicine-and-research/article3310674.ece
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... in an animal model
Every time I read the above phrase in a scientific paper, I get an image in my mind similar to this:
(http://monkeybrandz.com/wp-content/uploads/2011/05/hangover-2-monkey-in-a-dress-its-a-girl.jpg)
I just can't help it!
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Researchers have demonstrated that hematopoietic stem cells (HSCs) can be engineered to differentiate into HIV-specific cytotoxic CD8+ T cells capable of mounting a potent antiviral immune response that blocks HIV replication in a mouse model. The team, at the University of California, Los Angeles (UCLA) David Geffen School of Medicine, built on previous work demonstrating that human HSCs genetically modified with genes encoding a human HIV-specific T-cell receptor (TCR) can produce mature, fully functional T cells in human thymus implants in severe combined immunodeficient (SCID) mice.
However, while this prior research showed that the resulting CD8+ T cells were capable of killing HIV antigen-expressing cells ex vivo, the SCID-human mouse model demonstrates poor peripheral reconstitution and function of human immune cells, and so it wasn’t possible to evaluate the ability of the HIV-specific HSC-derived cytotoxic T lymphocytes (CTLs) to suppress HIV replication in vivo.
In their latest work the researchers took the technology a step further and introduced the genetically modified HSCs into a modified version of a humanized mouse model known as the nonobese diabetic (NOD)-SCID, common gamma chain knockout (γc−/−), humanized bone marrow, fetal liver, and thymus (the NSG-BLT) mouse model. These modified NSG-BLT animals can generate of peripheral human immune responses and represent an effective model for HIV infection and pathogenesis.
The results showed that HSCs carrying the HIV-specific TCR were capable of differentiating into CTLs that suppressed HIV replication in vivo and prevented or at least slowed HIV-related damage to the animals’ human tissues. Jerome A. Zack, M.D., and colleagues report their approach and experimental results in PLoS Pathogens in a paper titled “In Vivo Suppression of HIV by Antigen Specific T Cells Derived from Engineered Hematopoietic Stem Cells.”
The generation of CTLs that recognize viral antigens and kill virus-infected cells represents a critical component of the body’s natural antiviral responses. However, in the case of HIV infection, the CTL response fails to clear HIV from the body, and even when effective antiretroviral therapy (ART) is administered, the virus isn’t completely cleared. In fact levels of HIV-specific CTLs decline, probably because lower antigen levels fail to stimulate CTL persistence, the David Geffen researchers explain.
Their earlier studies demonstrated that TCR-modified human HSCs can be directed to develop into mature CTLs in mice engrafted with human thymus, in the context of the proper HLA type. Expanding on these findings, examined the ability of genetically modified T cells derived from HSC transduced with a single HIV-specific TCR to suppress viral replication in vivo.
NSG mice were implanted with human fetal liver-derived CD34+ HSCs that had been modified with a lentiviral vector carying the genes for a TCR targeting the HIV Gag SL9 epitope. Control HSCs were modified using a lentiviral vector containing a non-HIV-specific TCR with unknown specificity. The mice in addition received implants of human fetal thymus and liver under the kidney capsule. Initial analyses in this NSG-CTL model found that 53% of the CD45+ cells in the animals’ peripheral blood were of human origin, and there was a significant population of human CD34+ HSCs in the bone marrow, most of which co-expressed CD45, indicating they had lymphopoietic potential. The animals also generated significant populations of CD3-expressing T cells and CD19-expressing B cells in the bone marrow, indicating both that they were capable of multilineage human hematopoiesis and that other components of the human immune system were present in addition to T cells.
The NSG-CTL and control mice were then infected with an HIV-1 variant engineered with a tag that enables the detection of HIV-infected cells using flow cytometry. Within two weeks levels of infected cells were lower, and there was less initial CD4 depletion n animals implanted with the HIV TCR-expressing HSCs than the control animals. And although by six weeks both the HSC-CTL mice and control mice demonstrated overall increases in virus-expressing cells, HIV-specific TCR animals still demonstrated much lower levels of productively infected cells than the control mice, “indicating suppression of viral replication over time,” the team writes.
Moreover, at the six week post-infection time point mice containing cells expressing the HIV-specific TCR exhibited significantly greater preservation of CD4+ T cells and higher CD4 to CD8 T cell ratios than mice expressing the control TCR. “Thus, genetic modification of HSCs with a single HIV-specific TCR produces peripheral T cells capable of suppressing cellular HIV expression and CD4 depletion in vivo,” the investigators claim.
They separately assessed virus levels in the infected animals’ peripheral blood plasma using a novel quantitative PCR-based technique. This similarly confirmed that viral load at two weeks and six weeks post-infection was much lower in mice receiving the HIV-specific TCR HSCs than the control mice, which “suggested systemic suppression of HIV replication,” they add. Encouragingly, viral RNA analysis indicated that there had been no mutation of the specific SL9 viral epitope recognized by the TCR as a result of viral suppression.
In fact T cells expressing transgenic HIV-specific TCRs were found in multiple organs in mice receiving genetically modified HSCs, and when compared with control mice, these animals exhibited much lower HIV levels in the spleen, bone marrow, and human thymus implant. Evaluation of peripheral blood CTLs expressing the HIV-specific transgenic TCRs confirmed that the cells possessed an effector phenotype, including loss of CD45RA and CCR7 expression that was indicative of antigen-specific induction of cellular differentiation. Further assessment of HIV-specific CTL expansion indicated that the greater the initial reconstitution of transgenic HIV-specific cells, the more effective the control of viral replication at the six week time point.
“These studies provide a foundation and a model system that would allow the closer examination of human antiviral T-cell responses and the development of therapeutic strategies that target chronic viral infection,” the authors conclude. However, they point out, one apparent drawback with the humanized mouse model is that it demonstrates relatively limited immune responses to HIV. “The incomplete and varied immune reconstitution in the current humanized mouse systems results in differences in immune responses and kinetics of viral pathogenesis compared to natural HIV infection in humans,” they admit.
And while HIV replication rates and viral loads persisted in the mice, they also didn’t reach levels observed in natural infection in humans. This lower level of viral replication may be one reason why viral escape mutants to the SL9-specific TCR didn’t occur in the reported studies.
Nevertheless, they state, while natural antiviral T-cell immune responses are limited in current humanized mouse models, our studies suggest that the genetic programming of HSCs to produce T cells specific for HIV can overcome this limitation in this system and produce measurable T-cell responses that have a significant antiviral effect in vivo.
“We found it startling that the use of a single HIV-specific TCR can result in significant HIV suppression while natural suppressive antiviral CTL responses are polyclonal … These results strongly suggest that stem cell-based gene therapy may be a feasible approach in the treatment of chronic viral infections and provide a foundation towards the development of this type of strategy.”
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http://www.genengnews.com/gen-news-highlights/engineered-hscs-differentiate-into-hiv-specific-ctls-that-hold-back-hiv-infection-in-vivo/81246628/
Ann: they used humanised mice missy, not bonabos... ;D
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Every time I read the above phrase in a scientific paper, I get an image in my mind similar to this:
(http://monkeybrandz.com/wp-content/uploads/2011/05/hangover-2-monkey-in-a-dress-its-a-girl.jpg)
I just can't help it!
Is that a Vera Wang dress? Loving the pearls. She is fly!
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Is that a Vera Wang dress? Loving the pearls. She is fly!
"WorK"
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Ann: they used humanised mice missy, not bonabos... ;D
Oh noes! You mean like this?...
(http://www.costumestores.biz/images/35/mouse-adult-fancy-dress-mascot-costume203504765.jpg)
Is that a Vera Wang dress? Loving the pearls. She is fly!
I do believe it is - clutch the pearls! She certainly is rather fetching!
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I read about this back in 2009. A company called AdaptImmune is working on a similar thing, but I haven't seen any progress reports or the like, since I first read about it. I'm just very happy that other scientists are working in the same direction too. Just get on with it already, m'kay !!
* Adaptimmune announces clinical trial with engineered T cells (http://www.adaptimmune.com/2009/10/07/adaptimmune-announces-first-ever-clinical-trial-with-engineered-t-cells-designed-to-clear-hiv-infection/)
* ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00991224)
* Engineered killer T cell recognizes HIV-1's lethal molecular disguises (http://phys.org/news145458050.html)
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Oh noes! You mean like this?...
(http://www.costumestores.biz/images/35/mouse-adult-fancy-dress-mascot-costume203504765.jpg)
... or this?
(http://omg.wthax.org/super_mouse_wp.jpg)
;)
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;D
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... or this?
(http://omg.wthax.org/super_mouse_wp.jpg)
;)
That's the guy! ;D