The Tuberculosis, HIV, Selenium-deficiency, Positive Feedback Loop

                                                                 Introduction

            Understanding the tuberculosis-HIV-selenium-deficiency positive feed-back loop is critical to fully understanding both tuberculosis and HIV disease.

            HIV, tuberculosis, co-infection with hepatitis and other opportunistic infections; plus selenium nutritional deficiency, form a multi-focal positive feedback loop that increases inflammatory and oxidative damage as it concurrently depletes the body’s selenium supply. This results in a decline in both immune competence and the anti-oxidant defenses selenium supports. In his book What Really Causes AIDS Harold Foster described this phenomena as it relates to HIV alone as, “The Selenium-CD4 Cell Tailspin”. Monique van Lettow titled her book, “Triple Trouble: Tuberculosis, HIV Infection and Malnutrition”. Bemnet Amare referred to this as, the “Quadruple burden of HIV/AIDS, Tuberculosis, Chronic Intestinal Parasitosis and Multiple Micronutrient Deficiency”. I suggest opportunistic infections, hepatitis B and C, influenza A, and pneumonia all should be added to this multifaceted feedback loop to complete the causes of selenium hyper-deficiency and the resulting cytokine storm of oxidative stress and downward spiraling physiological dysfunction that severe selenium deficiency causes.  

            The essential trace element selenium is strategic for human health. Biologists refer to selenium as “the universally protective element”. It is the most essential element for the anti-oxidant system. That is because the molecule that forms the active site of the universal antioxidant glutathione peroxidase that helps maintain the health of all cells consists of selenium. Concentrated in the cells and organs of the immune system, selenium is critical to sustain proper immune function. Misunderstood or neglected by science for decades, selenium is chemically related to oxygen and sulfur, two other elements required for health and medicine.

            Many viruses, including HIV-1, HIV-2, hepatitis B and C, influenza A, Ebola-Zaire, polio, Coxsakie-B3, molloscum contagiosum and others, genetically encode and incorporate selenoproteins and thereby deplete the body’s selenium supply. Enveloped viruses attack the selenium supply stealing selenium molecules from the cells they infect, because they require it for viral replication. The HIV env/envelope gene encodes a selenoprotein. This suggests the probability that all enveloped viruses encode selenoproteins and assault the selenium supply of the cells and organs they infect. 

HIV’s attack on the immune system’s selenium supply progressively depletes the body of the selenium it needs to support anti-viral defense mechanisms. As viral load increases, selenium levels and CD4 count decline in tandem. Co-infection with other viruses likewise drains the body’s selenium reserves. For example, within three days of infection with influenza, selenium levels in cells lining the lungs fall by forty per-cent. That loss of immune competence in the lungs allows preexisting pneumonia mycobacteria to proliferate. Tuberculosis and pneumonia mycobacteria both genetically encode and require selenium. Activation of tuberculosis or infection with other pro-inflammatory diseases also deplete selenium reserves. Hepatitis, fungal and most opportunistic infections reduce selenium and subvert the body’s selenium supported immune defenses. This immunological subversion helps perpetuate their successful assault on the cells and organs they colonize.

            Early in the HIV epidemic scientists reported that CD4 count falls in tandem with selenium levels. Conversely, when selenium is supplemented, CD4 counts rise. Every scientist knows correlation does not prove causation. But close correlation does raise the question – is one factor causing the other effect? Is it a mere coincidence; or is there another factor in play? 

            Although many factors affect immune competency, no single constituent factor exerts more force than the level of selenium. Selenium affects all aspects of immune function. As one scientist explained, “If selenium levels are high, immunity will be high. If they are low, immunity will be low.” 

            Using HIV antiretroviral therapy (ARVs) and anti-tuberculosis drugs, both raise selenium levels. This is logical because reducing selenium depletion by viruses or mycobacteria should allow the body to gradually replenish the selenium pool.

            The positive feedback loop that exists among low soil/dietary selenium, HIV, hepatitis and other viral co-infections; tuberculosis and pneumonia mycobacteria; plus fungal and opportunistic infections works synergistically to drain the body’s pool of selenium. This increases both morbidity and mortality as the selenium level spirals downward.  By one scientist’s account, when a person loses 20% of their normal replete level of selenium, they develop AIDS or immunodeficiency. When they lose 30%, they die. Selenium is as essential as water to most cellular, and all animal and human life.

HIV Disease and Selenium

            Over the last thirty years numerous small clinical trials have demonstrated the benefit of selenium supplementation in both early and advanced HIV disease. The largest two studies are briefly described below.

            To confirm if selenium supplements are beneficial in early HIV disease, the Rwandan Ministry of Health sponsored a placebo controlled clinical trial of 200mcg selenium in three hundred antiretroviral-naïve HIV positive patients with between 400 and 650 CD4 count. After two years, “The rate of CD4 depletion was reduced by 43.8% among patients using selenium supplements.”   

            The benefit of selenium as an adjunct therapy in advanced disease was clearly demonstrated in a controlled clinical trial conducted by Harvard University and the Nigerian Institute for Medical Research on three hundred forty advanced AIDS patients with a baseline average of 50 CD4 count. Published at the 2006 Toronto XVI International AIDS Conference, this study showed that after sixteen months, the clinical arm that added 200mcg selenium to a three-drug HAART therapy increased hemoglobin by 30g/l compared to a 10g/l increase with HAART alone. In the selenium added group CD4 count increased 120 cells on average compared to 50 cells with HAART only. The authors noted that adjunct selenium therapy significantly reduced hospital visits for opportunistic infections and “weight gain was significantly higher in the selenium group.”

            Selenium supplementation is continuously beneficial in both early HIV disease and advanced AIDS. However it provides its most significant benefit in advanced disease when selenium deficiency becomes most critical.

            Supplementation with selenium has shown positive effect against numerous symptoms and conditions related to both HIV and tuberculosis. A review of the literature shows these include fatigue, anemia, lack of appetite, diarrhea, wasting, low body weight, disease progression, carcinogenesis, liver disease, nerve damage, pneumonia, depression, myopathy, cardiomyopathy, Kaposi sarcoma, candidiasis, skin problems, pancreatitis, arthritis and asthma.

            Although all human cells require selenium for both structural and functional purposes, selenium is concentrated in lymphocytes and erythrocytes – white and red blood cells. Erythrocytes require higher levels of selenium to protect them and blood vessels from oxidative damage caused by the oxygen molecules they transport. Since HIV progression leads to a decline in selenium, most HIV-related anemia should be considered “selenium-deficiency anemia.” HIV-related anemia should not be mistaken for iron deficiency anemia or treated as such. Iron is a pro-oxidant. Iron supplements increase HIV replication and should be strictly avoided in HIV therapy unless iron deficiency is first confirmed. Selenium supplements help against fatigue because they increase both hemoglobin levels and metabolism. Thus HIV and TB-related anemia should be remedied with selenium supplementation.

            Supplementation with selenium clearly increases CD4 count. It has also been shown to decrease CD8 count and improve CD4/CD8 ratio. These effects may be partially mediated through selenium’s effect inhibiting tumor necrosis factor-alpha (TNF-a) and nuclear-factor kappa-binding (Nf-kB); but more directly by increasing interleukin-2 (IL-2) and up-regulating the interleukin-2 receptor (IL-2r). As Marianna Baum explained, “selenium regulates levels of IL-2, the cytokine responsible for the earliest and most rapid expansion of T lymphocytes.”

            The entire sequence of where and how an increase in selenium exerts its effect in increasing CD4 count may not have been fully elucidated. That sequence may include improving thyroid function and increasing production of naïve CD4 cells from the bone marrow; and increasing IL-2 and up-regulating the IL-2 receptor. However since processing and differentiation of CD4 and CD8 cells takes place in the thymus, and this is where the switch in dominance from type-1 T-helper cells (TH1) to type-2 T-helper cells (TH2) also takes place; this is probably the primary location where the immune system collaborates to increase CD4 count and improve the CD4/CD8 ratio in response to a rise in the selenium level. Higher levels of selenium redirect T-cell processing and differentiation in the thymus away from production of CD8 cells and towards production

of CD4 cells. (Antioxid Redox Signal 2012;16:7:705-743)  

            In considering HIV treatment one must ask: precisely how do anti-retroviral drugs cause CD4 count to increase? ARVs suppress viral replication and that stops selenium depletion by the virus allowing selenium level in the body to replenish. Is that how ARVs increases CD4? Or do ARVs increase CD4 count through some other mechanism, allowing the increase in CD4 to stimulate an increase in selenium? Which effect causes the other? Or is there a third factor at play? While one can make an easy scientific argument for rising selenium levels stimulating an increase in CD4 count, there is no obvious explanation for the opposite effect. Thus, the way ARVs work to increase CD4 count must be by reducing viral drainage of the selenium pool. By suppressing viral replication ARVs allow a gradual increase in selenium levels to stimulate an increase in CD4 by improving cytokine messaging, especially via IL-2, and by redirecting lymphocyte differentiation within the thymus away from CD8 and towards CD4. 

Tuberculosis and Selenium

            Scientists report that HIV positive individuals with the lowest quadrant levels of serum selenium are three times more likely to develop active tuberculosis than those with the highest quadrant levels of selenium. Thus it seems logical, if you supplemented and raised the level of selenium in the body from the lowest to the highest quadrant, TB incidence potentially might fall by up to 60%. Raising selenium levels and reducing active TB incidence by even 30% to 40% would be a significant victory in the battle against active and multi-drug resistant TB, and save governments millions of dollars and improve public health. Adding selenium to the standard of care for TB might also shorten the period required for TB treatment. These untested hypotheses beg to be tested.

            While people with HIV are three times as likely to develop TB, those with less than 135 CD4 count are thirteen times as likely to develop active mycobacterial disease. Likewise, HIV positive subjects with active TB experience faster disease progression than those who do not have TB. A similar situation exists with regard to HIV and hepatitis. Those who are co-infected experience more rapid progression of each disease. What is the common factor connecting these phenomena?

            A review of the literature on tuberculosis and selenium reveals that; while selenium has been tested as a nutritional therapy for TB, it has never been tested at a “therapeutic”, mid to high-range dose. Second, selenium has never been tested as a monotherapeutic, adjunct therapy to standard TB treatment. When it has been tested; always in combination with other micronutrients; selenium has been used in the nutritional range of 100mcg to 200mcg. In contrast to past low-dose clinical trials, selenium supplementation for TB needs to be studied in the 400-1000mcg per day range. In pharmacology, dosage is key. Selenium supplements have never been tested singly in the correct therapeutic range against TB. Clinical trials are urgently called for to determine how much effect supplementing an adequate dosage of selenium may have.   

            Ebselen is a selenium-based drug proven to be, “a potent inhibitor of the mycobacterium tuberculosis Ag85 complex.” Thus it should have a positive effect against tuberculosis. It is unknown how the benefit of Ebselen compares to the benefit of using the correct therapeutic dose of selenium nutritional supplements.

            South Africa has the largest number of active TB cases in Africa and one of the larger caseloads of multi-drug resistant MDR TB. Lesotho has the highest per capita incidence of tuberculosis in the world. Both countries have low soil selenium content.

Developed more than forty years ago, the drugs used to treat TB today are less effective than they once were. As multi-drug-resistant strains proliferate and tuberculosis regains its hydra-headed preeminence as the dominant worldwide contagious disease, international health authorities plead for new effective drugs to battle this scourge. Few are in the pipeline. However, people with high levels of selenium seldom develop active TB. Why has this element not been tested at moderately high therapeutic doses to determine if it could help treat TB and reduce TB infection rates?  

Hemorrhagic Fever Viruses - Ebola, Lassa, and Yellow Fever - and Selenium

            Selenium is the only medication that demonstrated a direct effect in reducing mortality from Ebola-Zaire virus during the 2014 Ebola epidemic in West Africa. In the ELWA-ll Ebola Treatment Unit outside Monrovia, Liberia, overall survival rates quickly jumped from 44% to 68% once a moderate, therapeutic dose of 1.2mg of selenium a day was added to the established standard of care for supportive and symptomatic treatment. Unfortunately, 1.2mg was a suboptimal dose. Two milligrams should have been administered. That correct dose should have increased survival rates even more significantly.

            Selenium administered at two milligrams daily eliminated the death toll from an outbreak of Marburg virus in Angola. A dose of two milligrams per day, repeatedly has been shown to be effective in significantly reducing the mortality rate of other hemorrhagic fever viruses including Hantan virus in China. Will Taylor first sequenced the genetic code of Ebola-Zaire. He explains that what HIV-1 takes ten years to accomplish, Ebola-Zaire does in ten days. That is, HIV slowly - and Ebola extremely rapidly, collapses the selenium supply by genetically encoding selenoproteins that require selenium molecules. Since selenium has been shown to dramatically reduce death from several hemorrhagic fever viruses including Hantan virus, Marburg and Ebola; I suggest its potential use against two more common but less fatal hemorrhagic fever viruses; yellow fever and Lassa fever.  

            In both yellow and Lassa fever, most of those infected show no signs or symptoms of the disease. The minority who do, exhibit “flu-like” symptoms including pain, headaches, fever, fatigue and vomiting. Those symptoms easily can be confused with other diseases, so viral infection needs to be verified in a reference laboratory. People who are symptomatic for either of these hemorrhagic fevers usually recover after four or five days. The overall mortality rate is 3% to 7.5% in yellow fever, and 1.0% for Lassa fever.

            Yellow fever is caused by an enveloped, RNA, Flavivirus that infects over 200,000 and kills 30,000 annually, mostly in Africa. Yellow fever was the first virus proven to be transmitted by mosquitoes. In 1927 it was the first virus to be isolated. Yet even today, no specific treatment exists for yellow fever. After an incubation period of less than a week, symptomatic cases usually resolve after four or five days of acute illness. However in 15% of cases relapse occurs within six to twenty-four hours after initial recovery from the primary stage of illness. Relapse cases exhibit extreme jaundice, severe fever, organ failure and sometimes bleeding. Between 20% and 50% of the 15% of cases that relapse end in death, resulting in a 3% to 7.5% mortality rate.

            Lassa fever is a RNA, Arena-virus that infects more than 400,000 a year in West Africa resulting in 5,000 deaths annually. Following a six to twenty-one day incubation period, only 20% of those infected develop symptomatic disease. Although it has a relatively low mortality rate, approximately a quarter of symptomatic cases are left temporarily deaf, and another quarter permanently deaf. Lassa fever virus targets the selenium rich organs and cells of the immune system including lymphocytes, the liver, spleen and kidney; as well as vascular and placental tissue. This can cause organ failure in some, and a particularly high rate of mortality of about 90% in third-trimester pregnant women and 100% in late-term fetuses. This attack on the selenium supply results in lymphopenia, immune incompetence, and sometimes death.

            One question is whether a person’s initial selenium level might be a factor for determining who among those that get infected will exhibit symptoms, experience a more severe course of disease, or suffer fatality. 

Soil and Dietary Selenium

            Much of the world’s population is marginally deficient in selenium. The selenium content of agricultural soils is gradually diminishing due to the leaching effect of chemical fertilizers. According to soil scientists many parts of the world including much of Europe and the eight countries of Southern Africa are deficient in soil selenium. In fact Southern Africa could be considered a selenium semi-desert. Nutritional researchers have determined that 80% of the Malawian population is selenium deficient. At least 60% of the populations of seven other Southern African countries also eat a diet deficient in selenium. Soil deficiency is compounded by the fact that the dietary staple crop for most of Southern Africa is corn/maize. In most diets worldwide the largest source of selenium derives from the staple cereal-grain crop. Maize contains only half as much selenium as rice, and rice only half as much as oats, barley or wheat; the primary sources of selenium in Western diets. A maize-based diet tends toward selenium deficiency, especially when grown in selenium poor soil.

            Grains, meat and seafood are the primary sources of dietary selenium. With some exceptions, most fruits and vegetables are relatively poor sources. A maize-based diet low in meat or fish will be selenium deficient. People consuming this diet often exhibit mild to moderate nutritional deficiency of this essential trace element. This may explain the puzzling phenomenon in HIV therapy when certain patients taking ARVs do not regain immunity and vitality as expected. With a selenium deficient diet, their selenium reserves are not replenished sufficiently to adequately restore immunity, even though viral replication has been suppressed completely. Clinical trials are called for to determine if selenium supplements can remedy this.     

            Individuals with mild to moderate selenium deficiency have lowered immunity and are more susceptible to contracting both infectious and contagious disease and developing cancer. Population immunity is lower in countries with low soil selenium. That allows disease to spread more easily. Low bodily selenium caused by depletion due to disease or malnutrition increases the virulence and genetic mutability of viruses. Agriculturalists fortify livestock feed with selenium to raise herd immunity, prevent the spread of disease and improve fertility. No one provides human populations this benefit.

Where soil or dietary deficiency is an issue, many health experts suggest supplementing selenium to boost its content in human diets, improve population immunity and reduce cancer rates. This can be accomplished through adding selenium to table salt, maize meal, or agricultural fertilizers as some advanced countries do. A cost-benefit analysis points to fortifying table salt or maize meal. Supplementation should be a government health priority where selenium deficiency contributes to national health problems as in much of Southern Africa. However, when a specific person is ill, selenium tablets are the best solution. They can be added to any drug regimen.  

Conclusions and Recommendations

The tuberculosis-HIV-selenium-deficiency positive feedback loop poses a medical dilemma.  Selenium is the only medication besides ARVs proven to have a significant long-term impact against HIV disease. Yet most physicians have not studied selenium as adjunct or complementary therapy and are not informed what the safe or recommended dosage is for most cases. Dosage must be adjusted to the weight of the patient, but general guidelines can be proposed based on an average weight of 65kg. In early HIV disease a person with a CD4 count above 400 should take 200mcg daily. With CD4 in the 100 to 400 range, 400mcg may be considered. With CD4 count below 100, TB, or other opportunistic infections, 600mcg daily should be recommended. If an AIDS patient is in critical condition with pneumonia, organ failure, meningitis or encephalitis, 1mg should be used daily until the critical phase has abated. Administration of the medication should be in the morning. It  may disturb sleep if given in the evening. It does need not need to be in divided doses unless it is in the highest doses. Selenium is not contraindicated to any other medication and there are no negative side effects

            With active tuberculosis, 600mcg is normally called for. With inactive or suppressed TB, 200mcg daily is reasonable. Severe types of hemorrhagic fever virus disease such as Marburg or Ebola always require 2mg daily. This also applies to rebounded Lassa fever and yellow fever when symptoms are severe. In some cases, disease-related organ failure may be averted or aborted by utilizing high dose selenium in the range of 1-2mg daily. Selenium may accomplish this by redirecting the cytokine cascade away from a pro-inflammatory direction towards an anti-inflammatory route.        

            The final death knell for most people with AIDS or TB often comes in the form of either pneumonia or heart attack. Both can be related to the selenium hyper-deficiency caused by HIV, TB and their sequelae. Supplementing selenium may help delay or prevent both events. The selenium deficiency caused by the HIV envelope protein is central to understanding the pathogenesis of HIV. It is not a peripheral issue. Strictly speaking, health experts should no longer consider AIDS a “syndrome”, since the cause of the disease is well known. A good argument can be made for changing the name of the advanced stage of HIV disease to Acquired Immune Deficiency of Selenium (AIDS). That would help people recognize and understand a fundamental disease process associated with HIV infection that previously has been overlooked. A name change would also focus attention on an effective adjunct therapy for HIV and many other viral diseases. The fact that selenium supplements are not being used widely is disrespectful to both the science that supports it, and to the thirty-five million people currently infected. It is unethical for any reason to deny or withhold an effective complementary therapy that can slow disease progression and benefit the ten million HIV positive individuals worldwide who are currently receiving no treatment at all.           

            Selenium supplementation is certainly not the ultimate solution for HIV or TB. However it is a significant part of the solution for HIV disease and may contribute to quelling the rising tide of the tuberculosis pandemic and the threat posed by other emerging viruses such as Zika. It is urgent for governments or university research departments to conduct additional clinical trials against active TB using selenium at moderate to high therapeutic doses – 400 to 1000mcg per day. Who will be the first to conduct such a logic-based clinical trial that might revolutionizing anti-TB treatment? Why has this simple but promising strategy not been explored previously?

            Currently AIDS and TB are the most critical pandemics facing humanity. However an outbreak of a novel pandemic influenza with no existing population immunity that could kill hundreds of millions worldwide in less than a year - in every country on earth is overdue. Governments and international health organizations need to be prepared not just for the current battle, but also for the coming super-battle against a re-emerging 1920-like deadly flu pandemic. Selenium tablets can help reduce influenza-A infection rates, reduce intensity of flu symptoms, and reduce mortality rates when that world-shaking mega-pandemic eventually strikes. To prepare for such an epidemic, countries should maintain a strategic reserve of selenium tablets to help protect healthcare workers who, as in the Ebola epidemic, will suffer the greatest mortality of any employment group. Woe be the ministry of health that is not intelligently and logistically prepared for that viral catastrophe when it suddenly emerges. Healthcare staffs will be decimated. Be prepared.                                                                                                          

References

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The section covering yellow and Lassa fevers is based on information found in Wikipedia and the websites of the World Health Organization (WHO) and the US Center for Disease Control (CDC).