Differences between Stem Cells from the Placenta and Bone Marrow

Fazekasova et al. Mesenchymal stem cells were historically isolated from the bone marrow as an adherent stem cell population capable of “orthodox” differentiation, meaning that they have ability to become bone, cartilage, and fat. Further research revealed that these cells are also capable of “non-orthodox” differentiation, that is, becoming neurons, hepatocytes, insulin producing cells, and lung cells. Given the high number of growth factors secreted by mesenchymal stem cells, numerous companies have sought to develop therapeutic products from mesenchymal stem cells. For example, Osiris Therapeutics has been developing bone marrow mesenchymal stem cells as a treatment for Graft Versus Host Disease. Athersys has been using bone marrow derived mesenchymal-like cells for treatment of heart disease, and Mesoblast has been using these cells for treatment of bone injury.

A new generation of companies has been focusing other mesenchymal-like cells derived from other tissues. For example, Medistem Inc has identified endometrial regenerative cells (ERC), a type of mesenchymal-like stem cell that is found in the endometrium and appears to have higher ability to produce growth factors that stimulate new blood vessel production as compared to other sources of mesenchymal stem cells. General Biotechnology LLC has been developing tooth derived mesenchymal stem cells for treatment of neurological disorders. Celgene has been using placental-derived mesenchymal stem cells for treatment of critical limb ischemia, a disorder associated with poor circulation of the legs.

Given that there appear to be various sources of mesenchymal stem cells, an important question is how do these cells compare when they are used in experiments side by side. In a paper published this month, placental derived and bone marrow derived mesenchymal stem cells were compared. The scientists found that higher numbers of mesenchymal stem cells could be isolated from the placenta as compared to the bone marrow. Interestingly, placental mesenchymal stem cells were found to be comprised of both fetal and maternal origin.

One of the critical features of mesenchymal stem cells is that they are able to be used without need for matching with the recipient. This is because mesenchymal stem cells are historically known to be “immune privileged”. One of the experiments that the scientists did was to examine whether there is a difference between the bone marrow and placentally derived mesenchymal stem cells in terms of immunogenicity.

Placentally derived mesenchymal stem cells expressed lower levels of the immune stimulatory molecule HLA class I and higher levels of the immune suppressive molecules PDL-1 and CD1a, compared to bone marrow derived mesenchymal stem cells. However, when both cell types were treated with interferon gamma, the placentally derived mesenchymal became much more immune stimulatory as compared to the bone marrow cells. Furthermore it appeared that direct incubation with T cells resulted in higher T cell stimulation with the placental mesenchymal stem cells as compared to the bone marrow cells. Thus from these data it appears that bone marrow derived mesenchymal stem cells are more immune privileged as compare to placental derived cells.

Men with Type 1 diabetes eventually may have a way to grow their own pancreas transplants

Thomas H. Maugh II, Los Angeles Times

Researchers from Georgetown University Medical Center in Washington DC reported today at the Annual Meeting of the American Society of Cell Biology that sperm contains stem cells capable of becoming beta cells. The beta cells are the insulin producing cells of the pancreas which are damaged/destroyed in patients with Type 1 diabetes.

Conventionally adult stem cells are found in the bone marrow, fat tissue, and cord blood. Recent studies have identified stem cells in places such as menstrual blood (endometrial regenerative cells), hair follicles, and baby teeth. The finding that stem cells from sperm are capable of generating insulin-producing cells has several major implications. For one, males could theoretically bank their own stem cells and use them in the future. Currently transplants with beta cells or pancreatic transplants have the drawback that there are not enough donors and also that the recipient is required to receive life-long immune suppression.

The lead scientist of the finding is biochemist G. Ian Gallicano of Georgetown and his colleagues obtained tissue from human testes from recently deceased donors and placed them in a special growth medium in the laboratory, where they began producing insulin. “These are true pluripotent stem cells,” he said in a statement. When transplanted into the backs of immune-deficient mice, the cells cured diabetes for about a week before dying. More recent results, Gallicano said, show that the researchers are able to produce more insulin-producing cells and keep them alive longer. The challenge, he noted, is to make them survive for very long periods of time in the recipient.

Dr. Gallicano and his team previous published in the peer reviewed journal Stem Cells and Development (Golestaneh et al. Pluripotent stem cells derived from adult human testes Stem Cells Dev. 2009 Oct;18(8):1115-26) that the testes contains spermatogonial stem cells (SSCs) which are capable of converting to embryonic stem (ES)-like cells which can differentiate into all three germ layers and organ lineages.

The importance of the current research is that these stem cells can actually exhibit function when administered to animals. It will be interesting to see if other organ functions may be restored by use of these stem cells.

Mechanisms of a New Stem Cell Mobilizer

Jarcome-Galarza et al. J Bone Miner Res.

It is known that the bone marrow contains three main types of stem cells: a) hematopoietic stem cells, which make blood; b) endothelial progenitor cells, which maintain healthy blood vessels; and c) mesenchymal stem cells, which repair a variety of tissues and are capable of producing high amounts of growth factors. After major tissue injury or trauma all three of the bone marrow derived stem cells leave the bone marrow and enter systemic circulation in an attempt to heal the tissue damage. The original compound that was discovered to “mobilize” bone marrow stem cells was granulocyte colony stimulating factor (G-CSF). Studies in mice with lung injury in the late 1970s demonstrated that a lung-derived protein was capable of stimulating bone marrow to multiply and produce higher numbers of granulocytes. It was not until the late 1980s that scientists started injecting purified G-CSF into animals as a method of increasing the number of circulating stem cells. Why would people want to increase circulating stem cells? Commercially one of the main reasons is associated with the process of bone marrow transplantation. In bone marrow transplantation donors were historically required to undergo the painful procedure of bone marrow extraction, which requires an excess of 20 holes to be drilled into their hip bones. Compounds such as G-CSF could be administered to donors in order to make their stem cells enter circulation, and then the stem cells could be isolated from the blood instead of the bone marrow. This makes the procedure a lot less painful and arguably a lot safer. Additionally, the possibility of mobilizing stem cells by administration of a drug has the possibility of artificially increasing stem cell numbers in patients with degenerative diseases in order to attempt to naturally heal the condition.

The clinical use of G-CSF for mobilization and also for increasing granulocytes in the blood has resulted in multibillion dollars per year in sales for companies such as Amgen. Naturally, this has stimulated much interest in the process of how to make stem cells leave the bone marrow. G-CSF stimulates bone marrow stem cell release through several mechanisms. The main mechanism appears to be associated with stimulation of osteoclasts, which cause modulation of the bone marrow structure and physically release the stem cells from their environment. Other mechanisms exist such as breakdown of stromal derived growth factor (SDF-1). This protein is made by the bone marrow and literally keeps the hematopoietic stem cells stuck to the bone. When the bone marrow levels of SDF-1 decrease, the hematopoietic stem cells are no longer “stuck” to the marrow and as a result enter circulation. Yet another mechanism is that G-CSF activates neutrophils to produce various enzymes that cleave proteins on the bone marrow. These cleaved proteins are then recognized by pre-formed antibodies, which activate complement, which causes small holes in the bone marrow and thus releases stem cells.

The second “stem cell mobilizer” to be approved by the FDA is a drug called Mozibil which blocks the interaction between SDF-1 and its receptor CXCR4. This drug was sold by Anormed to Genzyme in a deal worth more than half a billion dollars. Mozibil is a superior stem cell mobilizer to G-CSF in many patients and as a result has rapidly been implemented clinically. Interestingly, it appears that Mozibil causes redistribution of different ratios of hematopoietic, mesenchymal and endothelial progenitor cells than G-CSF.

One of the most recent mobilizers under development is Parathyroid Hormone. This naturally –occurring substance has been demonstrated in clinical trials to mobilize stem cells, but apparently through a mechanism different than G-CSF and Mozibil. Specifically, both of these drugs appear to cause a temporary depletion of the stem cells in the bone marrow, whereas Parathyroid Hormone seems to preserve the stem cells inside of the bone marrow.

A recent paper (Jacome-Galarza et al. Parathyroid hormone regulates the distribution and osteoclastogenic potential of hematopoietic progenitors in the bone marrow. J Bone Miner Res. 2010 Dec 29) explored the activities of Parathyroid Hormone on osteoclasts in the bone marrow of mice. The authors found that treatment of mice with Parathyroid Hormone for 7 or 14 days increased the number of osteoclastic progenitors in the bone marrow as well as the absolute number of hematopoietic progenitors. These data suggest that the hormone acts not only as a means of stimulating redistribution of hematopoietic stem cells, but also may be involved in directly stimulating their multiplication, possibly through modulating activity of osteoclasts.

Stem cells in the Brains of Crayfish

Ayub et al. Dev Neurobiol.

Stem cells have been found in various organs to participate in repair after injury. For example, after a heart attack, cardiac specific stem cells that reside in the atrium are known to proliferate and cause repair of damage. In the brain stem cells participate in a variety of processes, for example stem cells in the dentate gyrus multiply in people who are mentally active. These cells appear to have reduced function in patients of depression. Interestingly, in depressed patients anti-depressants have been demonstrated to increase stem cell activity.

In a recent study (Ayub et al. Environmental enrichment influences neuronal stem cells in the adult crayfish brain. Dev Neurobiol. 2010 Dec 29) the effect of environmental stimulation on brain stem cells in crayfish was studied.

The scientists found that new brain stem cell development occurred in sexually differentiated procambarid crayfish by environmental enrichment. The studies also showed that environmental enrichment increases the cell cycle rate of neuronal stem cells. There was no effect of environment on the overall numbers of cells circulating in the hemolymph, enrichment resulted in increased expression of glutamine synthetase, a marker of the neuronal stem cells, in a small percentage of circulating cells; there was little or no expression of this enzyme in hemolymph cells extracted from deprived animals.

These data suggest that there seems to be a correlation between brain activity and brain stem cell activity in a variety of animals as well as in humans. By identifying chemical signals that control brain stem cell activity, it may be possible to develop “brain enhancing drugs”. One approach that has been attempted to do this is through administration of human chorionic gonadotrophin. This hormone is associated with pregnancy and is believed to be responsible for the pregnancy-associated neurogenesis that occurs in pregnant human women and mice.

While a study in stroke patients using human chorionic gonadotrophin did not demonstrate astonishing results, it may be possible to use this agent in more chronic situations of neurodegeneration such as Parkinson’s or Alzheimer’s disease.

Enhancing Efficacy of Bone Marrow Transplant

Huang et al. Blood. [Epub ahead of print]

Bone marrow transplantation has cured many patients of hematological diseases such as leukemias and lymphomas. Additionally, bone marrow transplantation is becoming used more and more in treatment of autoimmune diseases such as type 1 diabetes and multiple sclerosis. Unfortunately, there are still numerous limitations to this procedure. One of the biggest ones is that occurrence of graft versus host disease, in which the transplanted stem cells produce immune cells that attack the recipient. The other major problem is graft failure, in which the transplanted stem cells do not “take”.

The group of Dr. Ildstad from the University of Louisville has been working on enhancing bone marrow transplantation by co-administration of other cells called “facilitator cells.” In a recent publication (Huang et al. CD8{alpha}+ plasmacytoid precursor DC induce antigen-specific regulatory T cells that enhance HSC engraftment in vivo. Blood. 2010 Dec 29) it was shown that a type of dendritic cell, called the plasmacytoid dendritic cell, is capable of promoting bone marrow transplant efficacy through stimulation of T regulatory cells.

The scientists demonstrated that after bone marrow transplant from mismatched donors, there are immune suppressive cells, called T regulatory cells, that develop under specific conditions that stop the new (donor derived) immune system cells from attacking the recipient. When a mismatched bone marrow transplant is performed together with plasmacytoid dendritic cells, these cells “instruct” the donor immune system to generate T regulatory cells, which prevent graft versus host disease.

Implications of this research may be profound in areas outside of bone marrow transplantation for leukemias. In solid organ transplants, patients are required to take life-long immune suppressants to prevent the transplanted organ from being rejected. If donor bone marrow transplantation is performed with the donor organ, then the body does not reject the organ. Unfortunately this is not possible because bone marrow transplantation has a high risk of graft versus host disease. If the discovery of Dr. Ilstad’s group can be translated to humans, it may be possible to induce “immunological tolerance”, which is a state of immune un-responsiveness to the transplanted organ, while maintaining a functioning immune system towards pathogens and bacteria.

Resveratrol Suppresses Cancer Stem Cells

Pandey et al. Breast Cancer Res Treat.

Resveratrol is a compound found in grapes, red wine, purple grape juice, peanuts, and berries that has been associated with many health benefits, particularly reduction in heart disease. Some studies have demonstrated that resveratrol increases life span when administered at high concentrations. One area of controversy has been the potential of resveratrol in the treatment of cancer.

One way of testing the anti-cancer efficacy of compounds is to administer the compound of interest to cancer cells that are growing “in a test tube”, or “in vitro.” Recently it was shown that cancer cells taken from a patient and propagated in vitro are usually not representative of the original tumor from which the cancer cells were excised. Specifically, it has been shown that in patients, cancer cells can broadly be classified into the rapidly multiplying cells, and the “sleeping cells” otherwise known as tumor stem cells. It appears that in vitro the rapidly multiplying cells continue multiplying, but the cancer stem cells do not multiply. This is important because the cancer stem cells seem to be the cells responsible for causing the tumor to spread, whereas in the rapidly multiplying cells actually seem to be weaker and more sensitive to chemotherapy.

To date the majority of studies investigating effects of resveratrol on cancer have focused on testing with the rapidly multiplying cells. The paper published today investigated the effects of resveratrol on tumor stem cells. Breast cancer tumor stem cells where isolated based on expression of the proteins CD44 and ESA, and lacking CD24. Tumor stem cells were harvested from patients that were both estrogen receptor positive and negative. It was found that addition of resveratrol caused death of the tumor stem cells, as well as blocked their ability to form three dimensional tumors in tissue culture called “mammospheres.”

Interestingly it seemed like the effects of the resveratrol were mediated by manipulating the way in which the cancer stem cells make fat. Specifically, resveratrol caused a significant reduction in fat synthesis which is associated with down-regulation of the enzyme fatty acid synthase (FAS). The suppression of the enzyme FAS was correlated with upregulation of the genes DAPK2 and BNIP3, which are known to stimulate a process called “apoptosis”, or cellular suicide.

This recent paper belongs to a growing example of scientific reports in which various “treatments” advocated by naturopathic doctors seem to have effects on cancer stem cells. For example, a previous publication (Kakarala et al. Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat. 2010 Aug;122(3):777-85.) reported that the chemical curcumin, which is a component of the Indian spice turmeric, selectively inhibits cancer stem cells.

It appears that many of the chemotherapeutic drugs that are conventionally used in the treatment of cancer do not affect the cancer stem cell because chemotherapy requires tumor cells to be actively proliferating. In contrast, many of the “natural remedies” seem to suppress cancer stem cells because their activities seem to be mediated by other means than the ones in which chemotherapy works. It will be interesting to see if more papers such as the present one appear, which seem to provide scientific rationale for a more “compassionate approach” to cancer therapy

Increasing Efficacy of Stem Cell Therapy for Spinal Cord Injury

Jin et al. Spine (Phila Pa 1976).

Clinical trials of stem cells for treatment of spinal cord injury are currently being conducted in the United States and abroad. For example, the Covington Louisiana company TCA Cellular Therapy LLC is recruiting 10 patients with spinal cord injury to receive intrathecal infusion (lumbar puncture) of autologous, ex vivo expanded bone marrow-derived mesenchymal stem cells. Completed clinical trials have demonstrated some rationale that stem cells may be useful. For example, Kumar et al. (Autologous bone marrow derived mononuclear cell therapy for spinal cord injury: A phase I/II clinical safety and primary efficacy data. Exp Clin Transplant. 2009 Dec;7(4):241-8) reported on 297 spinal cord injury patients that were treated with their own bone marrow cells injected intrathecal. 33% of the patients reported an objective improvement.

As with other clinical trials of stem cell therapy, it appears that in the area of spinal cord injury there still remains room for improvement. We at Cellmedicine have reported a stunning improvement in a spinal cord injury patient by using a combination of CD34 and mesenchymal stem cells, which was recently published http://www.intarchmed.com/content/pdf/1755-7682-3-30.pdf. Unfortunately this was only one patient and more studies are required.

In an attempt to improve efficacy of stem cell therapy for spinal cord injury, a group from the Department of Neurosurgery, Spine and Spinal Cord Institute, at the Yonsei University College of Medicine, Seoul, Republic of Korea, has created an artificial method of increasing growth factor production from stem cells of the nervous system called neural progenitor cells. Previous studies have shown that neural progenitor cells are capable of treating several models of spinal cord injury, however their effects appear to be transient. Vascular endothelial growth factor (VEGF) is a protein that increases blood vessel production in tissues and has been previously demonstrated to stimulate integration of nervous system cells after spinal cord injury. Since increasing VEGF production could hypothetically increase efficacy of neural stem cells, a series of experiments were performed in order to generate modified neural stem cells which have enhanced VEGF production.

It is known that insertion of a gene into a cell can cause the cell to produce the protein made by the gene. So theoretically all the researchers had to do is to transfect (insert) the VEGF gene into the neural stem cells and the neural stem cells would be more effective. The problem with this is that too much VEGF can have negative effects. A more attractive approach would be to program the progenitor cells in such a manner so that they produce VEGF only when it is necessary. During spinal cord injury, the area of damage is associated with reduced oxygen, a condition called hypoxia. Ideally one would want to engineer the stem cells in a manner so that they produce VEGF only during times of hypoxia. One way of doing this is to control the expression the gene by using an inducible promoter.

Promoters are pieces of DNA that control expression of genes that are in front of them. Some promoters always turn on gene expression (these are called constitutive promoters), others turn on expression only under specific conditions (these are called inducible promoters. The promoter that turns on erythropoietin is an inducible promoter. Erythropoietin is made by the kidney and stimulates production of red blood cells. Its expression is turned on under conditions of lack of oxygen. This is why people who live in high altitudes have higher expression of erythropoietin. The scientists in the current publication developed a genetically engineered neural stem cell that contains the VEGF gene under control of the erythropoietin promoter. What this means is that the cells will be producing VEGF only under conditions of hypoxia. In order to selectively detect the areas of hypoxia, the scientists also developed stem cells that have the luciferase gene in front of the erythropoietin promoter. Luciferase is a protein that generates light and allows for easy detection in vitro and in vivo of the hypoxic cells.

The scientists found that the stem cells administered during hypoxia generated significantly higher concentrations of VEGF, which was associated with the promoter being turned on, as assessed by luciferase expression. Furthermore, rats receiving the VEGF expressing stem cells possessed a significantly lower amount of nerve damage and higher ability to recuperate after spinal cord injury.

These data suggest that it is feasible to combine inducible promoters with stem cells in order to augment various activities of the stem cells. This concept could be applied to numerous settings. For example, mesenchymal stem cells are known to selectively migrate to areas of inflammation. In the setting of cancer, mesenchymal stem cells could be transfected with genes that are encoding toxic substances. This way chemotherapy could be targeted only to cancer cells and therefore have a better safety profile.

Gene therapy has failed to a large extent because of lack of ability to control where the genes are administered. It may be possible that advancements in stem cell technologies will allow for a rebirth of gene therapy in that the stem cells may be used to deliver genes only to the tissues where they are needed.

Time to end stem cell institute CIRM

Wesley J. Smith , San Francisco Chronicle

The California Institute for Regenerative Medicine (CIRM) was created in 2004 as a result of the California Proposition 71, which called for a new bond issue to generate 3 billion dollars in order to support stem cell research in the State. In part, the institute was created as a response to President George W. Bush’s order restricting federal funding of embryonic stem cell research. The hope behind this enormous influx of cash to stem cell research was based on the popular belief that the State would have reduced medical costs, as well as treatments for many of the debilitating diseases that could benefit from stem cell therapy.

According to the author of the article, who is a senior fellow at the Discovery Institute’s Center on Human Exceptionalism and a consultant to the Center for Bioethics and Culture. “The CIRM hasn’t come close to fulfilling those promises. Here’s why California voters should reject the bond issue and shut the agency down in 2014…”

His rationale is that a) CIRM was created primarily to fund human cloning for research and embryonic stem cell research. So far, cloning has failed and embryonic stem cell cures, if they ever come, are a very long way off; b) Questionable uses of taxpayer’s funds. Specifically, $300 million went to help pay for plush research facilities, particularly those associated with board members of CIRM; c) Members of CIRM are paid exorbitant salaries. For example, the head of CIRM makes just under $500,000 a year, Art Torres, a board member and former chairman of the California Democratic Party, works four days a week – for a whopping $225,000 a year.

It is our opinion that basic research is critical for development of new therapies and for advancement of medicine. Therefore, conceptually, there is nothing wrong with supporting the use of taxpayer’s dollars for stem cell research. The issue that we have revolves around what research gets funded and how those projects are in line with the goals for which the funds were donated.

In the “drug development cycle” the first step is basic research and discovery of a biological mechanism of action associated with the disease. The second step is understanding how to manipulate the interaction. The third step is developing an intervention that may theoretically be useful and testing it in animal models of diseases. The fourth step, which is considerably more difficult, is to test the putative therapy in humans either at a low dose in healthy volunteers, or in terminal patients. This usually involves 10-40 patients and is formally called a Phase I clinical trial. Phase II clinical trials are the fifth step of developing a therapeutic. This involves 30-100 patients and assesses efficacy of the therapy in patients with disease. The last step of developing a drug involves conducting Phase III clinical trials, whose aim is to see whether the putative therapy induces therapeutic effects in a double blind, placebo controlled manner.

The majority of research funded by CIRM covers projects that are at the first to third steps, that is, from identifying new biological pathways, to trying to treat mice. Very few CIRM funded projects supported adult stem cell companies that are using their cells to treat patients. We anticipate that with more articles such as the one published by Wesley Smith, CIRM will become more cognizant of the reason why taxpayers supported the Institute: to develop cures faster. Indeed, one can see this increasing support in CIRM for adult stem cell companies in that in October of this year only 5 of 19 grants were for embryonic stem cell research.

International Stem Cell Corporation Expands Sales of Skin Care Product

North County Times – McClatchy-Tribune Information Services via COMTEX

The Oceanside California company International Stem Cell Corporation, (ISCO.OB) announced increased sales of its skin care product, the Lifetime Skin Care Line, which was associated with a 19% rise in stock price. In a press release, International Stem Cell Corporation stated “products are now being sold to subscribers of the investment newsletter of John Mauldin, founder of Millennium Wave Investments. The products were earlier offered to investors and others associated with International Stem Cell.”

The company has been developing a novel type of stem cell, called “parthenogenic derived” stem cells that has no ethical issues, yet appears to possess many of the properties associated with embryonic stem cells. Specifically, parthenogenic derived stem cells are generated by “activating” a human egg cell in absence of sperm. These cells multiply like embryonic stem cells, and possess the same ability as embryonic stem cells to generate all tissues of the body. The main therapeutic goals of the company are to develop islet cells for patients with diabetes, hepatocytes for patients with liver failure, and artificial corneas. However, given that approval from the FDA and other regulatory agencies is a long-term process, International Stem Cell Corporation has decided to leverage existing technologies into generating a product that can produce revenue without long-term research and development expenses.

By concentrating extracts that are produced by the parthogenic derived stem cells, the company has created stem cell-based products that are believed to be useful in skin care and restoration. On December 1st 2010, International Stem Cell Corporation announced the launch of its skin care product line which consists of a defensive Day Moisture Serum, and Recovery Night Moisture Serum.

“Because the quality products Lifeline Skin Care offers are experiencing strong demand and the human stem cell extracts require innovative manufacturing processes, we chose to develop our sales channels gradually and incrementally,” said Lifeline Skin Care CEO, Dr. Ruslan Semechkin.

International Stem Cell Corporation has historically been keen to develop products to market in order to generate ongoing revenue while its flagship products are under development. An example of this is the LifeLine research reagents company, which was developed by International Stem Cell Corporation as a means of selling products to researchers that are created as part of the company’s ongoing research and development program.

Stem Cell Transplant Cures HIV in “Berlin Patient”

Huffington Post

Timothy Ray Brown, also known as the “Berlin Patient,” received a bone marrow stem cell transplant in 2007 as part of a lengthy treatment course for leukemia. What was unique about Mr. Brown was that he was HIV positive. He now is HIV negative.

In the December 8th issue of the journal Blood, a scientific paper by Dr. Kristina Allers (kristina.allers@charite.de) entitled “Evidence for the cure of HIV infection by CCR532/32 stem cell transplantation” provided data documenting what is believed to be the first case of a human being cured of HIV by stem cell transplant.

HIV is known to kill patients by depleting an essential component of the immune system called the CD4 T cell. This cell is called the “helper cell” because it coordinates the antibody and cytotoxic arms of the immune response. HIV infection replicates within the CD4 cells and causes their death. Once patients lose their CD4 T cells they become highly susceptible to infections, which eventually results in their death.

Entry of the virus into CD4+ cells requires interaction with a protein called a “cellular receptor”. The main receptor by which HIV enters T cells is the CD4 protein. It was subsequently discovered that a second receptor is needed for the virus to enter, this second receptor can be either a protein called CCR5 or CXCR4. The importance of this “coreceptor” is that some people who are resistant to HIV infection have a different genetic make-up of the coreceptor which does not allow HIV entry. Molecular analysis of these people revealed that the specific CCR532/32 subtype was associated with resistance.

In bone marrow transplantation, the blood making stem cells (hematopoietic stem cells) of the recipient are destroyed by high dose chemotherapy/radiation, and new stem cells from the donor are administered. Theoretically, if the donor possesses the “resistance gene”, then the recipient should end up with CD4 T cells that are resistant to HIV infection.

In the recently published paper, doctors from the Charite Hospital in Berlin report the continued follow-up of the “Berlin patient”. The authors previously reported that the patient was HIV-infected but viral replication remained absent despite discontinuation of antiretroviral therapy after transplantation with stem cells from a donor containing the resistance-associated CCR532/32 mutation. It was expected that the long-lived viral reservoir would lead to HIV rebound and disease progression during the process of immune reconstitution. In the current report the doctors demonstrated successful reconstitution of CD4+ T cells throughout the body, as well as in the gut mucosal immune system following the stem cell transplantation, while the patient remains without any sign of HIV infection.

Interestingly, despite the fact that the patient appeared to be negative for HIV, a high proportion of activated memory CD4+ T cells were observed. These cells are known to be extremely sensitive to HIV infection. Furthermore, they demonstrated that during the process of the immune system re-establishing itself, they found evidence for the replacement of long-lived host tissue cells with donor-derived cells. The authors conclude by stating that “our results strongly suggest that cure of HIV has been achieved in this patient.”

While this protocol is theoretically useful for the cure of HIV, the major drawback is that there is a severe shortage of bone marrow donors in general, and specifically donors that have the HIV-resistance mutation. For this reason, companies such as Benitec, are using genetic engineering technologies in order to artificial produce such mutations. Under this scenario cells are taken from the bone marrow of an infected patient, stem cells are purified, and transduced with genetic material that artificially-cause this mutation.