Palliative Sedation is Not the Same as Euthanasia

Palliative sedation is a medical technique for terminally ill patients who cannot receive adequate pain relief while they are awake. Palliative sedation uses sedative medications to make the patient unaware and unconscious while the disease takes its course. This relieves extreme suffering by placing the patient in a kind of sleep. The sedative medication is gradually increased until the patient is comfortable and able to relax. Palliative sedation is not intended to cause death or shorten life (Erin Brender, MD; Alison Burke, MA; Richard M. Glass, MD. JAMA. 2005;294(14):1850.)

This has not stopped euthanasia advocates from asserting that palliative sedation is euthanasia. The inimitable Wesley Smith has a blog post on this and he refers to an article in the Journal of Pain & Palliative Care Pharmacotherapy that takes this deliberate conflation of these two very different things to the woodshed.  It’s a great read.  Check it out here.

Curing AIDS With Engineereed Stem Cells

Scientists from the UC Davis Health Science HIV team have demonstrated in a proof of principle study the safety and efficacy of transplanting HIV-resistant stem cells into mice.  If this protocol can be replicated in humans, it could signal a way to completely block HIV infection in human patients.

The human immunodeficiency virus (HIV) is a retrovirus.  The retroviruses contain an RNA genome, but once they infect the host cell, the RNA genome serves as a template for the synthesis of a DNA copy of the RNA genome.  The enzyme that performs this task is reverse transcriptase.  The DNA copy of the genome is inserted into the genome of the host cell.  This means that when the host cell divides, the viral DNA is passed to all of its progeny.

HIV infection causes acquired immunodeficiency syndrome (AIDS).  AIDS is characterized by a progressive shutdown of the immune system, which leads to life-threatening infections and cancers.  HIV infection occurs through the transfer of bodily fluids, such as semen, blood, vaginal fluid, saliva, or breast milk.  Sexual transmission, transmission from breast milk, contaminated needles, or from an infected mother to her baby at birth are the four main modes of transmission.  HIV screening of blood products has largely eliminated HIV transmission from blood products.

Since the discovery of AIDS in 1981, more than 25 million people have died from it, and even though antiretroviral treatments have decreased AIDS deaths and new infections, there were still probably at least 2.5 million new cases of AIDS in 2009.

HIV destroys the immune response by infecting helper T cells (CD4+ cells).  HIV can also infect dendritic cell and macrophages.  The mass die off of T helper cells prevents them from mediating cell-mediated immunity, and this makes the patient more susceptible to opportunistic infections.  People with untreated HIV infections usually develop AIDS and die from opportunistic infections or tumors.  Without antiretroviral treatment, someone with AIDS usually dies within a year.

In order to make HIV-resistant blood cell-making stem cells, Joseph Anderson and his co-workers engineered stem cells with three different genes.  First, they introduced into the stem cells, a human/macaque TRIM5 isoform.  In order to understand the significance of this gene, we must understand HIV more deeply.  When a retrovirus enters a host cell, it must “uncoat,” which simply means that the protein coating that surrounds the virus’ genome must be removed so that the reverse transcriptase can convert the RNA genome into a DNA copy.  Macaques are very widespread Old Word nonhuman primates that are immune the infection by HIV.  The reason for the immunity of these animals to HIV infection is that they possess in their cells a form of the TRIM5 protein that binds to bits of the HIV coat proteins and interferes with the uncoating process.  This prevents successful reverse transcription and transport of the viral DNA to the nucleus.  Therefore, the expression of the macaque version of TRIM5 is these blood-making stem cells rendered them resistant to HIV infection.

Secondly, the blood-making stem cells were given a gene that expresses a short hairpin RNA (shRNA).  These shRNAs can bind to the mRNAs are particular genes that prevent their expression.  In this case, the shRNA that was introduced into the blood-making stem cells prevented the production of the CCR5 gene product.  CCR5 is one of the cell surface proteins that HIV uses to gain entry into host cells.  Therefore, these blood-making stem cells will make blood cells that lacked the target for HIV infection.

Third, cells were engineered with a “TAR decoy.”  TAR is a site in the HIV genome that is bound by the HIV-encoded proteins Tat.  Tat binding to TAR activates expression of HIV genes.  However, by introducing TAR sites into the cells, Tat proteins inordinately bind to these non-functional TAR sites and not to the viral TAR site.  This will inactivate any HIV particles that happen to infect these cells.  With all these factors introduced into them, these blood-making stem cells and their progeny are completely resistant to HIV infection.

Introduction of these engineered stem cells into mice allowed these mice to resist infection even after experimental infection with HIV.  In the words of the lead author of this paper, Joseph Anderson, “After we challenged transplanted mice with live HIV, we demonstrated that the cells with HIV-resistant genes were protected from infection and survived in the face of a viral challenge, maintaining normal human CD4 levels.”  Remember the CD4 cells are the class of T cells that are specifically targeted by HIV, although the virus can infect other cell types too.

Anderson continued: “We actually saw an expansion of resistant cells after the viral challenge, because other cells which were not resistant were being killed off, and only the resistant cells remained, which took over the immune system and maintained normal CD4 levels.”  Anderson’s optimism, however, does not end there:  “We envision this as a potential functional cure for patients infected with HIV giving them the ability to maintain a normal immune system through genetic resistance.”  Anderson is an assistant professor of internal medicine and a stem cell researcher at the UC Davis Institute for Regenerative Cures.

This study confirms the safety and efficacy of this protocol, and validates the potential of this treatment for human HIV patients.  A grant application has been submitted by Anderson and his team for human clinical trials, and they are also pursuing regulatory approval for clinical trials.

Richard Pollard, the chief of infectious diseases at UC Davis (and a co-author on the study), said: “This research represents an important step in our fight against HIV/AIDS.  Clinical trials could give us the critical information we need to determine whether our approach truly represents a functional cure for a terrible disease that has affected millions and millions of people.”