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
References
Apr 1, 1984·Proceedings of the National Academy of Sciences of the United States of America·G M Church, W Gilbert
Apr 15, 1997·Proceedings of the National Academy of Sciences of the United States of America·M Kumar, G G Carmichael
Jun 6, 2000·The Journal of Experimental Medicine·J L RileyC H June
Jul 8, 2000·Proceedings of the National Academy of Sciences of the United States of America·R M Ribeiro, S Bonhoeffer
Aug 9, 2002·Nature·Ann M SheehyMichael H Malim
Aug 28, 2003·Journal of Virology·Leor S WeinbergerAdam P Arkin
Jun 15, 2004·Molecular Therapy : the Journal of the American Society of Gene Therapy·Laurent M HumeauBoro Dropulic
Jun 15, 2004·Journal of Virology·Xiaobin LuBoro Dropulic
May 28, 2005·Blood·Fumihiko IshikawaMine Harada
Aug 2, 2005·Nature·Marcel MarguliesJonathan M Rothberg
Aug 2, 2006·Proceedings of the National Academy of Sciences of the United States of America·Mitchell L SoginGerhard J Herndl
Nov 9, 2006·Proceedings of the National Academy of Sciences of the United States of America·Bruce L LevineCarl H June
Feb 15, 2007·PloS One·Jonas BinladenEske Willerslev
Jun 20, 2007·Nucleic Acids Research·Christian HoffmannFrederic D Bushman
Jul 4, 2007·Gene Therapy·L SchererM S Weinberg
Jul 31, 2007·Genome Biology·Susan M HuseDavid Mark Welch
Dec 11, 2007·Nature Biotechnology·John J RossiDonald B Kohn
Feb 12, 2008·Nature Methods·Micah HamadyRob Knight
Jun 20, 2008·Journal of Virology·Young Nam LeePaul D Bieniasz
Nov 11, 2008·Current HIV Research·José A Reyes-DariasAlfredo Berzal-Herranz
Mar 5, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Gary P WangFrederic D Bushman
May 9, 2009·PLoS Pathogens·Natasha WoodCathal Seoighe
Citations
Dec 12, 2012·Journal of Virology·Igor M Rouzine, Leor S Weinberger
Aug 13, 2011·Retrovirology·Bradford K Berges, Mark R Rowan
Apr 13, 2011·PLoS Computational Biology·Vincent T MetzgerLeor S Weinberger
Sep 3, 2010·PloS One·Janine KimpelR Paul Johnson
Dec 12, 2012·Virology·Ramesh Akkina
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
Dec 25, 2012·Blood·Pablo TebasCarl H June
May 14, 2016·Human Genetics·Ronald BenjaminMartin R Schiller
Nov 18, 2016·PLoS Pathogens·George J LeslieJames A Hoxie
May 7, 2016·PLoS Computational Biology·Luke I RastLeor S Weinberger
Oct 13, 2017·PLoS Pathogens·Rachel S LeibmanJames L Riley