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HIV Drug Linked To AIDS-Like Immunosuppression

What if the very drugs used to treat HIV infection are contributing to the development of AIDS?

So-called ‘antiretroviral’ HIV drugs in the integrase inhibitor category such as raltegravir and elvitegravir have been long touted as life-saving interventions, and yet, concerning new research indicates that they may not be living up to their promises. Published in Cell Death and Disease and titled, “HIV integrase inhibitor, Elvitegravir, impairs RAG functions and inhibits V(D)J recombination,” researchers at the Indian Institute of Science discovered that when mice were administered the drug elvitegravir, it resulted in significant reduction of mature B lymphocytes in 70% of mice studied.

Because the purported effect of HIV infection is disruption of the immune system, any treatment that is immunotoxic or immunodisruptive has the potential to worsen the condition and contribute to the diagnosis and progression of AIDS. Indeed, there has been a long history of criticism against the view that HIV infection alone is responsible for a set of 25 varied diseases which collectively comprise Acquired Immunodeficiency Syndrome (AIDS). The etiology of AIDS, like most syndromes, is multifactorial. Indeed, published studies have already implicated drug toxicity as a driver of AIDS deaths.1,2,3  For instance, according to Matt Irwin, MD:4

 “Many drugs regularly used to treat people diagnosed as HIV-positive have severe immunosuppressive effects, as well as other serious adverse effects. These include corticosteroids, AZT, other drugs in the same class as AZT, certain antibiotics, and protease inhibitors...corticosteroids induce immunosuppression that is claimed to be caused by HIV, with lowered CD4 counts and sparing of CD8 cells as well as sparing of antibody production.”

Another example of a conventional acknowledgement of this relationship is the 1996 edition of the United States Pharmacopeia's USP DI: Drug Information for the Health Care Professional which states:

"Because of the complexity of this disease state, it is often difficult to differentiate between the manifestations of HIV infection [sic] and the manifestations of zidovudine (AZT). In addition, very little placebo controlled data is available to assess this difference. (United States 1996, pages 3032-3034)”

While HIV is generally believed to only suppress the T-lymphocyte branch of the immune system, particularly the CD4+ T-helper cells, in 2011, a team of researchers at the US National Institute of Allergies and Infectious Diseases (NIAID) suggest that HIV damages the other half of the adaptive immune system, namely, the memory B-cells, which are responsible for recognizing previous infections and generating antibodies to them. B-cell function, therefore, may already be compromised in those fighting HIV infection. Anything that adds to this suppressive effect -- chemical, pharmaceutical, or biological -- would worsen the patient's condition. Indeed, if the new study applies to human physiology, we can expect that elvitegravir (and perhaps related drugs like raltegravir) may further damage the adaptive pole of the immune system of HIV patients, accelerating their demise. Not suprisingly, elvitegravir's drug insert lists a potentially lethal side effect of the drug as "immune reconstitution disorder" (IRD), also known as immune reconstitution inflammatory syndrome (IRIS). 

If pharmaceutical anti-HIV drugs are so toxic and ineffective, are there safer, more effective alternatives? We've indexed preliminary research on the topic on our HIV infections database, which include over 150 natural substances, including black seed which revealed powerful therapeutic properties in one exceptionally compelling case study we reported on here: Black Seed Extract 'Cures' HIV Patient Naturally..

For more information on the featured study in this article, read the following report titled, "HIV drug elvitegravir lowers the efficiency of immune system":

HIV drug elvitegravir lowers the efficiency of immune system

70% of mice tested showed significant reduction in B cell population

Progressive depletion of certain immune cell — CD4+ T-cell — populations along with impairment of cellular immunity is responsible for the onset of AIDS in the case of HIV-positive people. Now, researchers from the Indian Institute of Science (IISc) Bengaluru, have shown that two FDA-approved drugs (raltegravir and elvitegravir) used for treating HIV actually impairs the immune system to varying extents. Both these drugs are widely used and are part of the combination anti-retroviral treatment.

In the presence of the drug elvitegravir, the mature B cells responsible for immunity showed a reduction in animal studies. The reduction was pronounced — 70% of the mice studied showed a decrease in mature B cells.

The drugs target the HIV integrase protein that is responsible for the integration of viral DNA into human genome. HIV is a retrovirus which contains RNA instead of DNA. So when HIV infects human cells, the RNA is made into complementary DNA (cDNA) and this cDNA gets integrated into the human DNA. The viral DNA then makes copies of itself and then more viral particles are made, which then further infect more T cells.

Integrase and Rag1

Although integrase protein is specific to HIV, it shares structural and functional similarity with a protein present in humans called RAG1 (recombination activating gene 1). RAG1 is an integral protein of the immune system, and without it different antibodies cannot be developed leaving humans immune-deficient.

The team led by Prof. Sathees C. Raghavan from the Department of Biochemistry at IISc found that owing to the structural and functional similarity between the two proteins (RAG1 and integrase), the drugs designed to target HIV integrase protein can also bind and hamper the functions of RAG1 protein that is responsible for generation of antibody diversity leading to maturity of B cells of the human immune system. The results of the study were published in the journal Cell Death and Disease.

The researchers carried out in vitro studies using purified RAG proteins, and also studied the effects of the drug on human cell lines and on mouse models. In vitro studies showed the elvitegravir drug inhibiting binding and cleavage of human DNA in a dose-dependent manner. “Inside the lymphoid cells, DNA cleavage is important for the generation of antibody diversity. We found the drug significantly decreases the RAG1 function. When the drug binds to it and prevents DNA cleavage, it results in compromised antibody diversity,” says Prof. Raghavan.

While raltegravir drug did not cause significant inhibition of binding and cleavage of human DNA, these were impaired in the presence of elvitegravir drug. Cleavage inhibition was seen even at a low dosage of 50 microMolar, and “distinct” inhibition was seen when elvitegravir drug concentration was 200 microMolar.

“The structure of the two drugs is not the same. Elvitegravir drug probably binds tightly to RAG1 protein causing significant inhibition in cleavage,” says Namrata M. Nilavar from the Department of Biochemistry at IISc and one of the first authors of the paper. Mayilaadumveettil Nishana is the other first author of the paper.

“The elvitegravir drug caused significant effect on immune system when an extrachromosomal assay was used to study its effect inside the cells. We saw a threefold reduction in immune activity at 100 nanoMolar concentration and eightfold reduction at 1,000 nanoMolar concentration,” says Prof. Raghavan.

Mice models

Mice were treated with eight doses of elvitegravir drug at comparable dosage as used in humans. “We looked at how the drug affects the growth of different stages of B cells, which are responsible for robust immune system,” he recalls.

“In about 70% of animals we found significant reduction in B cell population, while 30% animals remained unaffected.”

“More studies have to be done before we can say that continued use of elvitegravir drug by HIV positive people may be counterproductive,” says Nilavar.

“In humans, the duration of treatment is longer. So the damage may be much higher. Based on our study we can say that use of elvitegravir may have side-effects on the immune system. Therefore, patients undergoing the treatment need to be monitored with utmost care,” Prof. Raghavan stresses."


References

https://link.springer.com/article/10.1007/BF01695694

2 https://www.ncbi.nlm.nih.gov/pubmed/7908356

3 https://www.ncbi.nlm.nih.gov/pubmed/2320079

4https://www.researchgate.net/publication/265187234_Low_CD4_T_lymphocyte_counts_A_variety_of_causes_and_their_implications_to_a_multifactorial_model_of_AIDS

 

 

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of GreenMedInfo or its staff.

Key Research Topics

Sayer Ji
Founder of GreenMedInfo.com

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