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HIV: “Functional vs. Immunological” Cure

A seminal article in the HIV field was published recently in PLoS Pathogens: March 2013:vol 9, issue 3, e1003211, doi:10.1371/journal.ppat.1003211. Investigators working with the hypothesis that the earlier an HIV infection is treated the better, reported that 14 individuals who received antiretroviral therapy within 1.1-2.1 months after infection, and continued for a median of 3 years, had undetectable plasma HIV concentrations for a median of  > seven years after discontinuation of all antiretroviral therapy. For want of a better term the investigators termed this long-term control of viral replication a “functional cure”. Studies of these individuals revealed very low levels of latent viral reservoirs, thereby indicating that early treatment thwarts the establishment of large viral reservoirs as commonly seen in individuals initiated on treatment long after infection has become established.  In this regard, viral cDNA was still detectable in peripheral blood lymphocytes, and when lymphocytes were stimulated in vitro via anti-CD3/28 and IL-2 + IL-7, mature viral RNA could still be detected, so that the investigators could not attribute the lack of detectable plasma HIV to a ‘real’ cure, i.e. eradication of the very last virus, the definition preferred by infectious disease experts. These data are important because they provide proof of principle that HIV infection can be cured, provided the residual viral infection after antiretroviral therapy can be reduced to a very low level, and provided the immune system has not been crippled by the initial infection. There are few, if any, microbial infections that can be cured by antimicrobials alone in an immunocompromized host. Antimicrobials can reduce the microbe numbers to very low levels, but an intact and normally functioning immune system is required to either keep the residual microbes in a latent state or to finally eradicate them. In the case of the many individuals chronically infected before antiretroviral therapy, it is now clear that we must achieve two goals: 1) reduce the residual virus to very low levels, and 2) direct therapy to the immune system to repair any deficiencies before it will be possible to achieve an “immunological cure”.

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Our Not-for-Profit Hospitals’ Profits

The March 4, 2013 issue of Time magazine has a superb and shocking article focused on the reasons for the accelerating health care costs in our country:

 

http://www.time.com/time/magazine/article/0,9171,2136864,00.html

 

The article points out that health care costs now comprise 20% of our Gross Domestic Product. To account for this huge expenditure, writer Steven Brill rightly points out that there are many economic sectors that have a stake in the health care ‘industry’, including the insurers, hospitals, doctors, pharmaceuticals, and lawyers. However, the most egregious of the profiteers in this “industry” are our hospitals, and especially our not-for-profit hospitals. Not-for-profit really is a euphemism for “not-for-taxes”. In addition, nonprofit hospitals have no shareholders. Consequently, our nonprofit hospitals are making huge operating profits, on the order of hundreds of million dollars/year. They enjoy making such gargantuan profits because they inflate the costs of every item used in that care of patients in a hospital stay by as much as 10,000-fold. Even more obscene are the salaries of the administrators of these profit centers, which account for a large share of the distribution of the profits. This article is a must-read for everyone. The irony is that in the 1960s when Medicare was under consideration, the AMA and doctors were aghast at the idea of “socialized medicine”. Now, fifty years later, doctors have lost their profession to the capitalists!

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IL-2 for GvHD: How can IL-2 both promote and suppress immune responses??

Recently, a friend of mine alerted me to an article that appeared in the New England Journal of Medicine entitled “Interleukin-2 and regulatory T cells in graft-versus-host disease” (vol. 365:2055, 2012). This report details the experience of the use of daily subcutaneous low dose IL-2 (0.3-3 x 106 IU/m2),compared with high dose IL-2 therapy used for cancer therapy (4.9 x 109 IU daily x 7), which itself causes severe toxicity via cytokine storm. A total of 29 subjects with chronic GvHD refractory to glucocorticoid therapy received IL-2 daily for eight weeks. Then, after a four-week hiatus, subjects who responded could receive IL-2 for an extended period. Of 23 evaluable subjects, 12 had major clinical responses involving multiple sites. The numbers of circulating CD4+IL-2Rα+FOXP3+ cells (T-Regs) were selectively increased in all subjects, with a peak median value at 4-weeks > 8-fold above baseline values (p < 0.001), without changes in other immunological parameters. Immunological and clinical responses were sustained in patients who received IL-2 for an extended period, permitting the glucocorticoid dose to be tapered by a mean of 60%.

 

The senior investigators of this study were Jerome Ritz and Robert Soiffer, old friends who were responsible for me becoming involved in their low dose IL-2 therapy trials more than 20 years ago (J. Clin. Onc. 9:2110, 1991). Therefore, I wrote to them, inquiring whether they thought that their results were compatible with the recent notion that one of the major molecular mechanisms of T-reg immunosuppression might be the degradation of IL-2 and other cytokines, as discussed by several groups of investigators in a Research Topic that I hosted and which was recently published in an eBook :

http://flashbook.frontiersin.org//clients/Frontiers/The%20Molecular%20Mechanisms%20of%20Regulatory/EBook.html

 

They wrote back that the ideas set forth in this Frontiers in Immunology Research Topic, that IL-2 initiates feed-forward promotion of immune/inflammatory responses, while simultaneously it initiates feedback inhibition of immune/inflammatory responses, is entirely consistent with the effects of low dose IL-2 in their subjects. Thus, I recommend all of these references to those interested in therapeutically altering immunity, either suppressing it or enhancing it.

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A Leukemia Breakthrough? Really? Are “engineered” TCRs the hope?

The New York Times recently reported on a “Breakthrough in the leukemia battle”. A scientific team led by Carl June at the University of Pennsylvania has been trying to “engineer” T lymphocytes (T cells), one of the two major classes of lymphocytes, that normally function to recognize and respond to invasion by foreign microbes, so that they can perform a similar role to rid our bodies of cancer. To do so, the team at UPenn used a virus similar to the Human Immunodeficiency Virus (HIV) to infect T cells from a young girl suffering from Acute Lymphoblastic Leukemia (ALL), to transfer genes coding for a T cell antigen receptor (abbreviated TCR) capable of recognizing a molecule termed CD-19, which is expressed on the surface of B lymphocytes, both normal and leukemic. Then these engineered cells are infused back into the patient, in the hopes that they will seek-out and recognize and react to the CD-19 molecules on the surface of the leukemia cells. Normally, T cells recognize foreign microbes in this way, and when they react, they produce “effector molecules” called cytokines or interleukins, which generate an inflammatory reaction, sometimes as severe as that seen in Toxic Epidermal Necrolysis (TEN). According to the Times’ report, this is exactly what happened to the young leukemia patient. She became so ill that it seemed sure that she would die very soon. Therefore, faced with a situation against the Hippocratic Oath, which teaches “first, do no harm” the physicians tried to rescue her by infusing antibodies reactive with interleukin-6 (IL-6), which is one of the most potent inflammatory molecules. Fortunately, this drastic last-ditch effort worked, and the youngster did not die, but went on to recover, apparently free of her diseased leukemia cells.

There are lessons to be learned from this case, the first is that if T cells express TCRs that are capable of recognizing and reacting with leukemia cells, they can effectively reduce the cancer cells to undetectable levels. Secondly, the ways by which T cells respond to leukemia cells are the same ways that they respond to foreign microbes, i.e. by producing interleukins that can result in severe inflammation, which themselves can be lethal. Essentially these molecules are responsible for “septic shock” seen in severe microbial infections. Thus, although sensational and provocative, I predict that this approach, i.e. of engineering T cells to become anti-cancer cells will not be “the magic bullet” envisioned by immunologists who want to “cure” cancer. However, it may be possible to learn from these human experiments, so that one can use them for therapy without toxicity, which is the challenge for the future.

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An “Immunological Cure” of HIV Infection?

The New York Times announced recently that an infant born to an HIV+ mother treated with antivirals within 30 hours after birth is “cured” of HIV infection. The baby was found to be HIV+ just after birth and was treated with a 3-drug combination for 18 months, after which the mother discontinued the drugs. When seen 6-months later the virus was undetectable in the blood. Other details remain to be reported, but if confirmed that the child’s immune system has contained residual virus, this case is important, because it is proof of principle that if the antivirals are given soon enough after infection, so that damage to the immune system does not occur, then any residual virus can be kept under control by a normal immune system, i.e. an “immunological cure”. Thus, current pediatrics treatment practices may be changed. As regards the vast majority of adults chronically infected with HIV who are taking life-long antivirals, the importance of this pediatric case is that it demonstrates that attention should now be shifted to the immune system, with immunotherapy designed to repair the damages inflicted by prolonged viral infection and the ineffectual immune response. It is clear now that the antivirals alone cannot repair the immune system, so that if that can be accomplished, immunological cures will allow the toxic antivirals to be eventually discontinued.

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Toxic Epidermal Necrolysis (Stevens-Johnson Syndrome)

Yesterday, I was contacted by an old friend who had a very sick patient with TEN or S-J Syndrome. I have been meaning to write about a new finding in this regard that was published in June ( McClusky et al. Nature 486:554, ’12; Reinherz Nature 486: 479, ’12-Commentary). The McClusky group from Australia showed with detailed structural studies that the well-known severe hypersensitivity syndrome that occurs in ~ 10% of patients who receive the HIV drug Abacavir, is due to the drug binding to certain MHC class II molecules, so that the drug alters the binding of self-peptides. This creates a situation of ‘altered self’, which the T cells recognize as foreign, thereby leading to a severe, systemic Type IV Delayed Type Hypersensitivity (DTH) reaction. As one might imagine, this syndrome comes with a high mortality rate. In addition to discontinuing  the offending drug and providing supportive care, one should think of drugs that block T cell-mediated immune reactions, such as the drugs that block IL-2 production (steroids, Cyclosporin-A, Tacrolimus) and drugs that block IL-2R signaling (Sirolimus). Also, effective might be the new anti-inflammatory drugs, such as TNFa inhibitors, IL-1RA, IL-6 blockers, and anti-IL-2R. Of course none of these drugs have been tested in clinical trials, because it is so difficult to perform clinical trials for such very ill patients in an ICU. I predict that many heretofore wierd hypersensitivity reactions to drugs as well as ‘spontaneous’ inflammatory syndromes will be found to have a similar etiology (i.e. DTH), and treatment (i.e. anti-T cell).

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The HIV/AIDS Dilemma

I am often asked why HIV/AIDS is such a problem and why there isn’t a vaccine or even a cure in sight after 30+ years of the epidemic. The simple answer regarding a preventative vaccine is that although it is fairly simple to generate a vaccine using the wonders of modern genetic engineering, it is very difficult to ethically test a vaccine to demonstrate that it works! Think about it. Would you volunteer to be a recipient of a new experimental HIV vaccine? Even if the vaccine carried no risks of untoward side effects, exposure to it would render your immune system no longer virgin territory, so that testing for the possibility of HIV infection by surveying for HIV antibodies would no longer be possible. Also, it is unethical to test the efficacy of the vaccinees by exposure to HIV! Therefore, the only avenue available for vaccine experimenters is to wait to see whether you might become infected ‘naturally’. That might take a decade, a lot of volunteers and a lot of money! Therein lies the HIV vaccine problem. The solution lies in devising a therapeutic vaccine a la Pasteur’s rabies vaccine, because it is much easier to test vaccine efficacy in individuals who are already infected, by simply discontinuing their anti-retroviral drugs for a brief period, 3-6 months, to see if the immune system can contain the residual virus, and prevent it from replicating. If so, then this would be the vaccine to move into prophylactic clinical rials in normal volunteers.

The ‘cure’ problem is even more vexing. Most current HIV scientists and clinicians feel a priori that a cure is impossible, in that if one has become infected, it is because the natural immune system has failed, and therefore one cannot hope to ever eradicate the virus from the body. However, therein lies the problem. After many infections, especially from the herpes virus family, the immune system never completely clears the virus. Instead, the immune system keeps the virus in a latent, or hidden state. Thus, in order to work towards a cure, the therapy must be directed toward repairing and enhancing the function of the immune system, so that after the anti-retroviral drugs have reduced the viral ‘load’ to a very low level, the immune system can keep it that way, in a latent, non-dangerous state.