- 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.
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.
Structural and functional similarity:
- 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.
in vitro studies:
- 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.
- 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,
- The elvitegravir drug caused significant effect on immune system when an extrachromosomal assay was used to study its effect inside the cells.