HIV integrase inhibitor, Elvitegravir, impairs RAG functions and inhibits V(D)J recombination

Nishana, Mayilaadumveettil and Nilavar, Namrata M and Kumari, Rupa and Pandey, Monica and Raghavan, Sathees C (2017) HIV integrase inhibitor, Elvitegravir, impairs RAG functions and inhibits V(D)J recombination. In: CELL DEATH & DISEASE, 8 .

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Abstract

Integrase inhibitors are a class of antiretroviral drugs used for the treatment of AIDS that target HIV integrase, an enzyme responsible for integration of viral cDNA into host genome. RAG1, a critical enzyme involved in V(D)J recombination exhibits structural similarity to HIV integrase. We find that two integrase inhibitors, Raltegravir and Elvitegravir, interfered with the physiological functions of RAGs such as binding, cleavage and hairpin formation at the recombination signal sequence (RSS), though the effect of Raltegravir was limited. Circular dichroism studies demonstrated a distinct change in the secondary structure of RAG1 central domain (RAG1 shares DDE motif amino acids with integrases), and when incubated with Elvitegravir, an equilibrium dissociation constant (K-d) of 32.53 +/- 2.9 mu M was determined by Biolayer interferometry, leading to inhibition of its binding to DNA. Besides, using extrachromosomal assays, we show that Elvitegravir inhibited both coding and signal joint formation in pre-B cells. Importantly, treatment with Elvitegravir resulted in significant reduction of mature B lymphocytes in 70% of mice studied. Thus, our study suggests a potential risk associated with the use of Elvitegravir as an antiretroviral drug, considering the evolutionary and structural similarities between HIV integrase and RAGs.

Item Type:	Journal Article
Publication:	CELL DEATH & DISEASE
Additional Information:	Copy right for this article belongs to the NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	12 Aug 2017 06:51
Last Modified:	12 Aug 2017 06:51
URI:	http://eprints.iisc.ac.in/id/eprint/57624

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