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There is a new class of HIV drugs, derived from plants that inhibit the enzyme protein kinase CK2 (formerly casein kinase II). The name of this new class of HIV drugs is CK2 inhibitors. It is interesting that protein kinase CK2 is not a HIV enzyme, it is a human enzyme. The flavonoid quercetin is probably the premier member of this class, because it is relatively safe, found in many plants, particularly members of the onion family and is cheap and commonly available including by mail order on the World Wide Web. If the word "quercetin" is typed into almost any search engine, many sites will be located that sell quercetin products.

There is a large, sophisticated and complex body of research on protein kinase CK2 (formerly casein kinase II), the flavonoids and of course HIV itself. This article will not delve into these complexities but instead seeks to assemble the relevant research papers to provide guidance for the immediate treatment of people with HIV. The interested reader is referred to the relevant research papers for more precise details. There are over 40 million people in the world with HIV including myself and we feel the urgent need for improved treatments. I also describe in this article some in-vivo experiments and my hypothesis and conclusions.

Protein kinase CK2 is an ancient and ubiquitous holoenzyme which has been highly conserved in evolution. The CK2 subunit genes have a calculated unit evolutionary period close to 30 million years [1]. The flavonoids themselves have probably existed for over one billion years in vascular plants [15]. Thus there has been a long history of co-evolution of plants and animals. This evolutionary process has produced what is essentially a natural anti-viral - quercetin. This anti-viral has already been exquisitely engineered by a billion years of evolution. Once the interaction with vitamin C was observed the tasks were simply to observe the behaviour of both substances - quercetin and vitamin C, in order to determine appropriate dosages and to identify the relevant research papers. The side effects are very obvious, so it was relatively easy to arrive at interesting conclusions just by observing them. All that is required is an understanding of biology at an intermediate level, including the basics of the HIV life cycle and the basics of enzymes and enzyme inhibition.

Experiment Analysis

Experiment 1 firstly implies that there is an interaction between quercetin and vitamin C that creates a drug, because side effects are observed. This is supported by a report [16] for the polio virus and one would reasonably expect it to also be true for HIV. Vrijsen et al [16] hypothesize that quercetin must be ascorbate stabilized. The half-life of vitamin C is approximately 4-5 hours, but I observed in experiment 1 that the stimulant effect lasted several hours. I propose the following alternative hypothesis. This could be easily confirmed in a laboratory.

The aglycone form of quercetin binds to ascorbic acid to form the glycoside form of quercetin.

This hypothesis is supported by the fact that glucose and ascorbic acid are very similar in structure. I obtained this fact from the book "Nutrition Almanac" by Gayla J. Kirschmann and John D. Kirschmann (McGraw-Hill) in the section on Vitamin C.

Most animals in fact manufacture ascorbic acid in the liver from glucose with a four enzyme cascade. The final enzyme in the cascade is L-gluconlactone oxidase. Humans are one of the few animals that lack this enzyme. I located this fact at the following site on the World Wide Web:

Molecular Expressions - Ascorbic Acid Gallery

Secondly, experiment 1 implies that absorption is occurring. It has been reported [5] that quercetin glycosides are absorbed through the glucose transport pathway in the small intestine. Thus it is probable that vitamin C is reacting with quercetin in the stomach to form a glycoside form which is then absorbed through glucose transport layers in the small intestine.

Thirdly, experiment 1 implies that quercetin is reaching its target - the protein kinase CK2 enzyme, at least in cells of the brain and heart. Protein kinase CK2 is reported to be plentiful in both the brain and the heart [1],which may account for the headache and the tachycardia. The ringing sound in the head in particular confirms that the CK2 target is reached because of the report of protein kinase CK2 activity in auditory neurons [11]. My dramatic improvements in T4 cell count indicate that quercetin is also reaching its target in cells of the immune system, particularly T4 cells. The dry mouth and the muscle aches are probably due to interaction of vitamin C with some other components of the Hay Fever and Sinus formula. When the target is reached, it implies that absorption into the cell is occurring.

The headache that was experienced in experiment 1, the ringing sound in the head, the insomnia and the stimulant effect observed in all experiments are strong evidence that quercetin crosses the blood brain barrier.

Experiments 2 to 5 all provide evidence that quercetin is stored in the body. It took repeated experiments before I finally made that realization during experiment 5 and it was a Eureka moment. This insight is explained by the report [6] that 98% of quercetin in human plasma is protein bound. Although it was known that quercetin binds to blood proteins, it was not known that it can bind for a long time and will remain in the body and repeatedly cycle for a long time if vitamin C is ingested.

Experiments 3 and 5 where I observed sweating in the arm pits were very interesting. The arm pits contain many lymph nodes and the lymph nodes are known to harbour HIV. What exactly is occurring in this situation needs to be elucidated

Experiment 5 suggested that quercetin interacts with protease inhibitors and I subsequently abandoned them. I found that quercetin can only be combined with reverse transcriptase inhibitors. This is my personal observation and opinion only, and expert advice is needed to resolve this issue.

It was interesting in experiment 5 that although my T4 cell count improved dramatically, my viral load was still detectable. I suspect that there was viral resistance to the combination of other HIV drugs that I was using, since I had been using that combination for many years. Thus although high-level replication was greatly reduced by quercetin, low-level replication was continuing. High and low level replication will be explained in a later section of this article.

Experiments S1 - S3 suggested to me that spirulan which is a substance in the herb spirulina is also a CK2 Inhibitor because it has very similar side effects to quercetin and has been shown to have anti-HIV activity in the laboratory [9]. It is interesting that spirulan is not even a flavonoid, it is a sulphated polysaccharide. 

Spirulan also appears to behave in a very similar manner to quercetin, so I came to the following conclusions which must be confirmed in the laboratory:

Quercetin Cycle

I propose the following model (hypothesis) of the quercetin cycle. In the following section when I use the word "quercetin" I am referring to what is normally called the aglycone form.

There are 3 binding sites on the quercetin molecule. The reference cited is the reason for postulating the binding site.

Phase 1 Dosing

Phase 2 Dosing

Cycle

Fig 1  Logical Diagram of the Quercetin Cycle

Viral Resistance

An implication of the fact that protein kinase CK2 is a human enzyme is that it is highly unlikely that CK2 inhibitors in general will suffer from the classic problem with all currently approved HIV drugs - viral resistance, because human enzymes do not mutate. Quercetin has been shown to bind directly to the  a catalytic sub-unit of CK2 [8]. Thus in most circumstances only one drug in this class may be necessary. I propose that quercetin is the ideal choice. There is also evidence [10] as one would expect, that inhibition of protein kinase CK2 will make HIV much less capable of developing resistance to existing HIV drugs. Another implication is that sub-optimal dosing will not risk the development of viral resistance to CK2 inhibitors themselves, but it will afford more opportunity for HIV to develop resistance to the existing drugs, so optimal dosing is desirable.

Effects on HIV of Protein Kinase CK2 Inhibition

The following cellular and HIV enzymes and structural proteins have been shown to be phosphorylated by protein kinase CK2 and thus indirectly inhibited by CK2 inhibitors. None of these proteins is completely inhibited, since they will function even if phosphorylation does not occur, but at a much reduced rate.

Cellular proteins involved in HIV-1 transcription. [2]

Reverse transcriptase, p66 and p51. [8]

All three of the enzymatic activities of reverse transcriptase have been shown to be stimulated by CK2 in vitro [8], namely the following:
RNA-dependent DNA polymerase (RDDP) 2.8 fold increase
DNA-dependent DNA polymerase (DDDP) 4.1 fold increase
Ribonuclease H (RNase H) 3.9 fold increase

HIV-1 Rev has been shown to stimulate oligomeric CK2 catalysed phosphorylation of p99 up to 7.2-fold [13].
HIV-1 Rev may be an effective potent activator for the CK2 catalysed phosphorylation of the following HIV-1 gene products [13]
external envelope protein, gp120,
reverse transcriptase p51,
transmembrane domain of envelope protein, gp41.
capsid protein, p27 and p17.
The CK2 mediated stimulation of RT (p66) activity may be unrelated to the cellular level of Rev in HIV-1 infected cells.

Protease enzyme, p11. 3 fold increase [7]

The following HIV-1 gene product has been shown to be "potently inhibited" by quercetin, which implies it is phosphorylated by CK2.[4]

Integrase

The following HIV-1 gene product has been shown to be inhibited by quercetin, which implies it is phosphorylated by CK2.[14]

Vpr 

Vpr induces cell cycle abnormality, causing cellular accumulation at G2/M phase and increased ploidy. Viral replication increases more than 2-fold in cells arrested at G2/M phase [14].

Logical Diagrams showing effects of various treatment combinations.

The following diagrams show the situation where there is no viral resistance. When there is viral resistance to the inhibitors there will be a "leak" through the inhibitor block. It is impossible for HIV to become resistant to the CK2 inhibitor, so there will never be a "leak" through the CK2 inhibitor block. The "pro virus" is the integrated HIV genes in the infected cell chromosomes.

Fig 2   Infected cell untreated

Fig 3   Infected cell treated with reverse transcriptase inhibitors.

Fig 4   Infected cell treated with reverse transcriptase inhibitors plus protease inhibitor.

Fig 5   Infected cell treated with reverse transcriptase inhibitors plus CK2 inhibitor.

Fig 6   Uninfected cell treated with reverse transcriptase inhibitors.

Fig 7   Uninfected cell treated with reverse transcriptase inhibitors plus protease inhibitor.

Fig 8   Uninfected cell treated with reverse transcriptase inhibitors plus CK2 inhibitor.  

Inhibition of Both Alpha and Alpha' Catalytic Sub Unit Of Protein Kinase CK2

High and Low Level Replication

One would expect that syncytium formation would be greatly reduced if not eliminated. Syncytium form when large amounts of HIV gp120 protein coat the cell surface due to budding virus. The gp120 protein then binds to CD4 receptors on adjacent cells and the cells fuse to form giant cells - syncytium. If most or all cells are converted to low level replication, then there will be greatly reduced gp120 on the cell surface and thus less likelihood of cell fusion. The research on spirulina [9] provides some support for this conclusion.

CK2 Substrates

There are more than 160 proteins that are potential or confirmed substrates for CK2 in the nervous system in the following categories [1].

Substrates involved in signal transduction pathways and protein synthesis
Cytoskeletal, structural and adhesive proteins
Transcription factors and associated proteins
Enzymes involved in nucleic acid synthesis
Other nuclear and nucleolar proteins

This may seem a little daunting, but there is a very complex system of biochemical interactions between CK2 and other chemicals in the body. Experience has shown that side effects are relatively mild. Although the complexities of the biochemistry may not be completely understood, I argue that this should not be a barrier to using natural CK2 inhibitors. Mankind used fire for millions of years without understanding it. Every living thing on earth has been engineered by evolution. We certainly don't completely understand even the biochemistry of the human body, but we still use our bodies. Experience should be the determining factor in light of the urgency of the current HIV epidemic. Quercetin is in onions! Most people have quercetin in their bodies from their diet and many people take vitamin C. The strategy is to simulate what happens in nature. 

Vaccine

One theoretical possibility that must be investigated is that treatment with quercetin before or after exposure may render a form of immunity. If HIV is immediately deprived of use of the CK2 enzyme, the body may be able to develop natural immunity to any given strain of HIV.

Quercetin Behaviour

The behaviour of quercetin reflects the long history of co-evolution of plants and animals. There has been a report that the movement protein of the tomatovirus tobomovirus appears to be phosphorylated by a host protein kinase similar to CK2 [12]. This suggests that plants have evolved CK2 inhibitors like quercetin because they also are infected by viruses that utilize CK2 like enzymes. Animals may have evolved to take advantage of these plant anti-virals. Quercetin is in many plants, but is relatively rare. Consequently animals have evolved to store quercetin and accumulate it, because it is so valuable as an anti-viral against a whole class of viruses.

Additionally quercetin binds to blood proteins and is stored when there is not a large amount of vitamin C in the blood, since it is not necessary to suffer the side-effects if there is no infection. Most animals when they are sick will manufacture large amounts of vitamin C in the liver, which will then bind to the blood bound quercetin to begin the quercetin cycle. Once an infection has resolved, the liver no longer manufactures so much vitamin C, so quercetin no longer cycles and once again binds to blood proteins.

Other Known CK2 Inhibitors

The following have been named as CK2 inhibitors [8].
Neocarzinostation-chromophore (NCS-chrom)
Glycyrrhentinic acid derivative (oGA)
Epigallocatechin gallate (EGCG)

Future Possibilities

The dry mouth I experienced in experiment 1 was very severe, and I also noticed an effect on my sinuses. On a number of occasions I noticed that a dose of vitamin C by itself would result in a very dry mouth and an effect on my sinuses.  I did not experience these side-effects in later experiments with the lymphodram.

Many years ago I received an injection of liquorice root extract which gave me muscle aches. Thus I strongly suspect that the muscle aches I experienced in experiment 2 were due to the Glycyrrhiza glabra component of the Hay Fever and Sinus Formula. The muscle aches lasted throughout that overdose week

These observations suggest that other flavonoids may also behave like quercetin and have 3 binding sites. One binding site for blood proteins, one for ascorbic acid and the third binding site that would characterize the flavonoid by the enzyme it binds to. In fact most flavonoids have a glycoside form. The properties for quercetin that I have described in this article may be class properties for the flavonoids.

This opens up many interesting possibilities for the future because there are over 4000 known flavonoids!

The properties I have described for spirulan are also probably class properties for the sulfated polysaccharides.

***** Do not experiment with herbs by adding vitamin C or calcium without the supervision of a qualified medical professional.*****

There is a herb used in Chinese medicine to treat alcoholism called Radix puerariae [3]. This herb contains the isoflavones daidzin and daidzein. These isoflavones may also treat drug addiction including possibly nicotene addiction. The herb red clover (Trifolium pratense) also contains daidzein in the root of the herb. (Nutrition Almanac) Daidzein is a flavonoid and must be dosed in the same manner as the flavanoid quercetin - with Vitamin C and phase 1, phase 2. Please refer the "Dosing" section of this web site. All flavonoids must be dosed in this manner. I understand daidzein can be obtained from the company www.TwinLab.com in the United States of America. Please consult your doctor before taking daidzein.

There are also flavonoids that may be useful in the treatment of many cancers [3]. In fact quercetin has been shown in experiments to strongly inhibit the growth of breast, prostate, colon, ovarian, kidney, stomach, lung, skin and leukemia cancers [3]. There may also be other cancers that are inhibited by quercetin. The mechanism of inhibition is almost certainly by  inhibition of protein kinase CK2 because quercetin has been shown to bind to the alpha catalytic sub-unit of CK2 [8]. When cancers are inhibited, the immune system may well be able to destroy the cancer cells.

Because quercetin is a CK2 inhibitor, other CK2 inhibitors will probably also inhibit these cancers. Spirulan which is in Spirulina and is described in this article, may also inhibit all these cancers because it is also a CK2 inhibitor.

Because Quercetin binds to the Alpha' catalytic sub-unit of protein kinase CK2 and Spirulina binds to the Alpha catalytic sub-unit of protein kinase CK2, combining both Quercetin and Spirulina with their respective co-factcors will result in very strong inhibition of CK2 and more rapid shrinking of cancers. Refer to "Dosing" Section of this Web Site for dosing information.

Other conditions that may be treated by flavonoids include coronary heart disease, alcoholic lever disease, influenza and a whole class of viruses that use protein kinase CK2  [3]

The following herbs are very interesting and should be investigated. They are available in Health Food Stores and Vitamin Stores. They are probably dosed with the same dose of Vitamin C as quercetin. (refer Dosing Section)

Brahmi - Bacopa monniera - improves memory.
Goto Kola - Centella asiatica - improves mental acuity.
Bilberry - Vaccinium myrtillus - improves vision.
Pau D'Arco - Tabebuia neptaphylla - anti-fungal
Valerian - Valerian officinalis - sedative.
Raspberry leaf - Rubus idaeus - helpful in childbirth.
Golden Seal - Hydrastis canadenis - anti-bacterial.
Echinacea - Echinacea purpurea - treatment of the common cold and flu.

There may be a flavonoid in the following herb that slows the loss of telomere length, thus promoting longevity:

Schizandra - Schizandra Chinensis - longevity?

I have heard that the American Indians know of herb that can make you younger. One possible explanation for this may have to do with the telomeres. When a sperm fertilizes an egg a zygote is formed. This zygote inherits the chromosones from the father and mother, including the telomeres which which are shortened by ageing in the parents. There may be an enzyme in the zygote and developing embryo that once again lengthens the telomere. The flavonoid in the American Indan herb may be involved in allowing this enzyme once again to function even in an adult and once again lengthen the telomeres.

The following herbs almost certainly have useful contraceptive flavonoids:

Wild Yam Root - Dioscorea villosa - contraceptive.
Queen Anne's Lace seed - Daucus carota - contraceptive.
Pomegranate - Punica granatum - contraceptive.

The following common herbs can be fairly easily obtained:

Reference: Herbs, their cultivation and design. Authors: John and Rosemary Hemphill. Publisher: Lansdowne

Sage - Salvia officinalis - antiseptic, improve memory. There may be 2 useful flavonoids in this herb. It is claimed that when rubbed on teeth it will whiten them. This herb could be ground with vitamin C and rubbed on teeth to see if there is any effect.

Thyme - Thymus vulgaris - antiseptic

Fennel seeds - Foeniculum vulgare dulce - anti-wrinkle?. It is not clear whether the flavonoid in this herb should be used internally or externally.

Yarrow - Archillea Millefolium - baldness. It is claimed that a wash, presumably to the head slows balding. Once the flavonoid is isolated, it may be possible to use this orally if it works.

Rosemary - Rosmarinus officinalis - memory.

Chamomile - Anthemis Nobilis - relax and calm. This herb is available as a herbal tea. It is quite mild. Tea could be made, allowed to cool to luke warm and 1 gram of crushed vitamin C could be mixed in. Heat destroys vitamin C. The tea is then ready to drink. This can be done with any herbal tea, but some of the Chinese herbal teas are quite dangerous if taken this way. You are at your own risk if you experiment in this way with herbal teas.

Hyssop - Hyssopus officinalis - treatment of intestinal worms.
Tansey - Tanacetum Vulgare - expels worms.

Kelp is available in Vitamin stores and as a marine plant should be tested for sulfated polysaccharides.

The traditional use of herbs is a guideline to what the flavonoids or suflfated polysaccharides in the herbs are useful for.

The following two web sites list European and Chinese herbs and the traditional use of the herbs. The botanical names are also given. There is an enormous number to select from, but they do need to be researched and tested.

www.botanical.com

www.drshen.com

The following book is a comprehensive and detailed reference book on herbs which also lists the traditional medicinal use of the herbs:

A Modern Herbal. Author: Mrs M. Grieve FRHS. Publisher: Merchant

Illnesses that are micro-nutrient deficiency should be treated with micro-nutrients, not flavonoids or sulfated polysaccharides. For instance high blood pressure is a deficiency of vitamin B3, however there are flavonoids that will also lower blood pressure. In this situation it is preferable to use vitamin B3. Quite a few people suffer various strange maladies, but if there is not obvious infection, these maladies are probably micro-nutrient deficiencies. The simple approach is to put these people on a super micro-nutrient program because this will help them in multiple ways. Please refer to the article "Optimum Nutrition" in the Editorial of this web site. If they are still suffering a problem, it may be easier to diagnose and there may be a useful herb. For instance Golden Seal listed above is a strong anti-bacterial. The herbs I have listed above have no micro-nutrient equivalent.

Spirulina is blue-green algae and is usually found associated with coral. Marine plants and particularly marine algae should be tested by adding calcium for sulfated polysaccharides. There are a large number of marine algae in the ocean. The seaweed used in Japanese cooking and other seaweed used in cooking in particular should be tested by adding calcium.

There are plants used in Chinese cooking that may be of interest. They are dried mushrooms, wood fungus and lotus root which should be tested with calcium and vitamin C. These plants are available in Chinese herbal stores and supermarkets. These plants should be boiled for 10 minutes and allowed to cool. The liquid will contain sulfated polysaccharides that are powerful anti-virals and anti-bacterials. Crushed calcium can be added, and a tablespoon of the liquid can be taken, but don't do this. Let the regulatory agencies test these. A source has told me that lotus root contains a sufated polysaccharide that will strip off the coat of viruses. Lotus root also contains some interesting flavonoids. The mushroom family in general may contain a great many interesting sulfated polysaccharides and shold be tested with calcium.

Even common vegatables and fruit, both leaf, root and seed contain a great many flavanoids. Brocolli, Cauliflower, Spinach, carrot, potato, beetroot, parsnip and all the fruits etc. should be tested for flavanoids. Quercetin is extracted from onions, so these should be taken seriously.

Although it may seem that there needs to be alot of clinical trials by the regulatory agencies for flavonoids and sulfated polysaccharides, top statisticians from universities could be consulted for advice about shorter, smaller yet reliable clinical trials. I understand a good clinical trial only needs 100 people and does not need to be double blind placebo.

Regulatory agencies might consider the Co-operative Democratic Organization Model in the Editorial of this web site. Productivity and efficiency greatly improve with this model. A source has informed me that profitability at least doubles. Vitamin and Herb companies might also consider this model.

Regulatory agencies should also charge the vitamin and herb companies for clinical trials. Perhaps a charge per bottle of approved herb or flavonoid sold in their country.

Summary

The fundamental problem with HIV is its utilization of the human CK2 enzyme. CK2 inhibitors address this problem at its source. All other treatments operate downstream of the fundamental problem and are ultimately swamped by highly replicating virus. CK2 Inhibitors will undoubtedly prove highly efficacious in combination with existing HIV anti-virals. The fact that they will also not suffer from viral resistance is a wonderful bonus.

HIV's hi-jacking of the human CK2 enzyme is it's strength, but also its weak point, it's Achilles heel. The plant strategy of blocking this one part of the viral machine that is both very destructive and not subject to rapid mutation is an example of the finesse of Mother Nature. If you prefer a more scientific statement it is the finesse resulting from a billion years of evolution.

Acknowledgements

I gratefully acknowledge the assistance of my nephew William Bovill Jr. B.Sc.(Hons) in retrieval and clarification of the existing research. All errors or inconsistencies are entirely my own responsibility. Although I acknowledge Bill's assistance, all original material, hypothesis, insights and this whole web site are entirely my own work.

Note

All diagrams modelled and rendered with the free software package Blender3d.

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