HIV sequence variation associated with env antisense adoptive T-cell therapy in the hNSG mouse model.

Molecular Therapy : the Journal of the American Society of Gene Therapy
Rithun MukherjeeFrederic D Bushman

Abstract

The first use of lentiviral vectors in humans involved transduction of mature T-cells with an human immunodeficiency virus (HIV)-derived env antisense (envAS) vector to protect cells from HIV infection. In that study, only a minority of the patient T-cell population could be gene-modified, raising the question of whether the altered cells could affect replicating HIV populations. We investigated this using humanized NOD/SCID IL-2Rgamma(null) (hNSG) mice reconstituted with approximately 4-11% envAS-modified human T-cells. Mice were challenged with HIV-1(NL4-3), which has an env perfectly complementary to envAS, or with HIV-1(BaL), which has a divergent env. No differences were seen in viral titer between mice that received envAS-modified cells and control mice that did not. Using 454/Roche pyrosequencing, we analyzed the mutational spectrum in HIV populations in serum-from 33 mice we recovered 84,074 total reads comprising 31,290 unique sequence variants. We found enrichment of A-to-G transitions and deletions in envAS-treated mice, paralleling a previous tissue culture study where most target cells contained envAS, even though minority of cells were envAS-modified here. Unexpectedly, this enrichment was only detected after the ...Continue Reading

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Citations

Dec 12, 2012·Journal of Virology·Igor M Rouzine, Leor S Weinberger
Apr 13, 2011·PLoS Computational Biology·Vincent T MetzgerLeor S Weinberger
Apr 22, 2015·Molecular Therapy : the Journal of the American Society of Gene Therapy·Rachel S Leibman, James L Riley
Jul 16, 2014·Trends in Biotechnology·Timothy NottonLeor S Weinberger
May 14, 2016·Human Genetics·Ronald BenjaminMartin R Schiller

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