A recent paper describing the engineering of stem cells to generate HIV-specific CD8 T cells has drawn considerable media attention and, regrettably but not untypically, many of the stories are profoundly misleading. Examples of headlines include:
“Scientists engineer stem cells which suppress HIV: cure for AIDS possible”
“New breakthrough shows stem cells can be engineered to fight HIV!”
“UCLA-engineered stem cells seek out and kill HIV in living organisms”
The last example is the headline of the UCLA press release that accompanied publication of the paper in PLoS Pathogens. It is not inaccurate, but what is likely not apparent to many people is that just about everyone’s stem cells make CD8 T cells with HIV-specific T cell receptors (TCRs) that would have similar potential to suppress HIV replication in humanized mice (the model used in the study). My stem cells have probably made some while I’m writing this post and the same is true for anyone reading it. Although some TCRs appear particularly adept at recognizing HIV antigens, it is not the lack of HIV-specific CD8 T cells with appropriate TCRs that underlies the inability to control HIV replication in most people; rather, the preponderance of evidence indicates that the functionality of the HIV-specific CD8 T cell response is severely compromised.
The PLoS Pathogens paper does discuss some of the potential reasons for this lack of CD8 T cell function, but omits any direct reference to the one most researchers consider crucial: the lack of functional HIV-specific CD4 T cell help. Over the last couple of decades it has become clear that the generation and maintenance of effective CD8 T cell responses is almost always dependent on help from CD4 T cells (and it is uncertain if the rare descriptions of CD4-independent CD8 T cell responses are relevant to people, or reflect the artificiality of the specific model systems used). HIV-specific CD4 T cells have been show to be preferential targets for HIV infection, and these responses are weak and dysfunctional in the vast majority of HIV-positive people (with the notable exception of many elite controllers). The UCLA approach to generating HIV-specific CD8 T cells via stem cell modification may represent a technical achievement, but it has little prospect of being therapeutically useful if there is not also a strategy to address HIV-specific CD4 T cells. Used alone, the results would be expected to mirror those achieved in prior studies where HIV-specific CD8 T cells were infused directly into people with HIV; the cells trafficked to the sites of HIV replication, showed some transient activity, and then became as dysfunctional as the many HIV-specific CD8 T cells that were already present.
While this analysis may sound very pessimistic, there are approaches that might address the HIV-specific CD4 T cell part of the equation. The genetic modification of CD4 T cells to make them resistant to HIV infection by eliminating CCR5 expression—an approach developed by Sangamo BioSciences and currently in clinical trials—is an example. Carl June, one the trial investigators, has long-term plans to combine the Sangamo treatment with gene-modified HIV-specific CD8 T cells. At the moment the CD8 T cells are genetically altered in the lab and re-infused as opposed to introducing the modification via stem cells; a phase I trial is ongoing at the University of Pennsylvania. Because there is evidence that some CD8 T cell TCRs may work better than others, there might be potential benefits to combining HIV-resistant CD4 T cells and CD8 T cells with souped-up TCRs (as June ultimately plans to do). The UCLA technique of introducing TCRs by modifying stem cells has several advantages compared to manipulating the CD8 T cells directly, so it’s not as if the study is without merit, it’s just unfortunate that the near-term therapeutic implications of the work have been severely exaggerated in the media coverage.
PLoS Pathog 8(4): e1002649. doi:10.1371/journal.ppat.1002649
Scott G. Kitchen1, Bernard R. Levin1, Gregory Bristol1, Valerie Rezek1, Sohn Kim1, Christian Aguilera-Sandoval2,3, Arumugam Balamurugan4, Otto O. Yang2,3,4, Jerome A. Zack1,2,3
1 Division of Hematology-Oncology, The David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America, 2 Department of Microbiology, Immunology, and Molecular Genetics, The David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America, 3 The UCLA AIDS Institute, The David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America, 4 Division of Infectious Diseases, Department of Medicine, The David Geffen School of Medicine at UCLA, Los Angeles, California, United States of America
The HIV-specific cytotoxic T lymphocyte (CTL) response is a critical component in controlling viral replication in vivo, but ultimately fails in its ability to eradicate the virus. Our intent in these studies is to develop ways to enhance and restore the HIV-specific CTL response to allow long-term viral suppression or viral clearance. In our approach, we sought to genetically manipulate human hematopoietic stem cells (HSCs) such that they differentiate into mature CTL that will kill HIV infected cells. To perform this, we molecularly cloned an HIV-specific T cell receptor (TCR) from CD8+ T cells that specifically targets an epitope of the HIV-1 Gag protein. This TCR was then used to genetically transduce HSCs. These HSCs were then introduced into a humanized mouse containing human fetal liver, fetal thymus, and hematopoietic progenitor cells, and were allowed to differentiate into mature human CD8+ CTL. We found human, HIV-specific CTL in multiple tissues in the mouse. Thus, genetic modification of human HSCs with a cloned TCR allows proper differentiation of the cells to occur in vivo, and these cells migrate to multiple anatomic sites, mimicking what is seen in humans. To determine if the presence of the transgenic, HIV-specific TCR has an effect on suppressing HIV replication, we infected with HIV-1 mice expressing the transgenic HIV-specific TCR and, separately, mice expressing a non-specific control TCR. We observed significant suppression of HIV replication in multiple organs in the mice expressing the HIV-specific TCR as compared to control, indicating that the presence of genetically modified HIV-specific CTL can form a functional antiviral response in vivo. 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.