HIV-1 CCR5 Gene Therapy Will Fail Unless It is Combined with a Suicide Gene

Overview

Journal Sci Rep

Specialty Science

Date 2015 Dec 18

PMID 26674113

Citations 7

Authors

Aridaman Pandit

Rob J De Boer

Affiliations

Soon will be listed here.

Abstract

Highly active antiretroviral therapy (ART) has successfully turned Human immunodeficiency virus type 1 (HIV-1) from a deadly pathogen into a manageable chronic infection. ART is a lifelong therapy which is both expensive and toxic, and HIV can become resistant to it. An alternative to lifelong ART is gene therapy that targets the CCR5 co-receptor and creates a population of genetically modified host cells that are less susceptible to viral infection. With generic mathematical models we show that gene therapy that only targets the CCR5 co-receptor fails to suppress HIV-1 (which is in agreement with current data). We predict that the same gene therapy can be markedly improved if it is combined with a suicide gene that is only expressed upon HIV-1 infection.

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References

Bonhoeffer S, Coffin J, Nowak M . Human immunodeficiency virus drug therapy and virus load. J Virol. 1997; 71(4):3275-8. PMC: 191463. DOI: 10.1128/JVI.71.4.3275-3278.1997. View

Sasson S, Kelleher A . Site-specific host gene modification by zinc finger nucleases: pointing the way to drug free control of HIV-1?. Clin Transl Immunology. 2014; 3(7):e19. PMC: 4232064. DOI: 10.1038/cti.2014.12. View

Tebas P, Stein D, Tang W, Frank I, Wang S, Lee G . Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014; 370(10):901-10. PMC: 4084652. DOI: 10.1056/NEJMoa1300662. View

Lee C, Dang J, Joo K, Wang P . Engineered lentiviral vectors pseudotyped with a CD4 receptor and a fusogenic protein can target cells expressing HIV-1 envelope proteins. Virus Res. 2011; 160(1-2):340-50. PMC: 3495169. DOI: 10.1016/j.virusres.2011.07.010. View

Marin V, Cribioli E, Philip B, Tettamanti S, Pizzitola I, Biondi A . Comparison of different suicide-gene strategies for the safety improvement of genetically manipulated T cells. Hum Gene Ther Methods. 2012; 23(6):376-86. PMC: 4015080. DOI: 10.1089/hgtb.2012.050. View

Caruso M, Klatzmann D . Selective killing of CD4+ cells harboring a human immunodeficiency virus-inducible suicide gene prevents viral spread in an infected cell population. Proc Natl Acad Sci U S A. 1992; 89(1):182-6. PMC: 48200. DOI: 10.1073/pnas.89.1.182. View

Rossi J, June C, Kohn D . Genetic therapies against HIV. Nat Biotechnol. 2007; 25(12):1444-54. PMC: 4539027. DOI: 10.1038/nbt1367. View

Allers K, Hutter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E . Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood. 2010; 117(10):2791-9. DOI: 10.1182/blood-2010-09-309591. View

Okoye A, Picker L . CD4(+) T-cell depletion in HIV infection: mechanisms of immunological failure. Immunol Rev. 2013; 254(1):54-64. PMC: 3729334. DOI: 10.1111/imr.12066. View

10.

Huelsmann P, Hofmann A, Knoepfel S, Popp J, Rauch P, Di Giallonardo F . A suicide gene approach using the human pro-apoptotic protein tBid inhibits HIV-1 replication. BMC Biotechnol. 2011; 11:4. PMC: 3224247. DOI: 10.1186/1472-6750-11-4. View

11.

Hutter G . More on shift of HIV tropism in stem-cell transplantation with CCR5 delta32/delta32 mutation. N Engl J Med. 2014; 371(25):2437-8. DOI: 10.1056/NEJMc1412279. View

12.

Althaus C, Joos B, Perelson A, Gunthard H . Quantifying the turnover of transcriptional subclasses of HIV-1-infected cells. PLoS Comput Biol. 2014; 10(10):e1003871. PMC: 4207463. DOI: 10.1371/journal.pcbi.1003871. View

13.

De Boer R . Which of our modeling predictions are robust?. PLoS Comput Biol. 2012; 8(7):e1002593. PMC: 3405990. DOI: 10.1371/journal.pcbi.1002593. View

14.

Wodarz D, Nowak M . Mathematical models of HIV pathogenesis and treatment. Bioessays. 2002; 24(12):1178-87. DOI: 10.1002/bies.10196. View

15.

de Boer R, Perelson A . Target cell limited and immune control models of HIV infection: a comparison. J Theor Biol. 1998; 190(3):201-14. DOI: 10.1006/jtbi.1997.0548. View

16.

De Boer R, Ribeiro R, Perelson A . Current estimates for HIV-1 production imply rapid viral clearance in lymphoid tissues. PLoS Comput Biol. 2010; 6(9):e1000906. PMC: 2932679. DOI: 10.1371/journal.pcbi.1000906. View

17.

Grossman Z, Meier-Schellersheim M, Paul W, Picker L . Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nat Med. 2006; 12(3):289-95. DOI: 10.1038/nm1380. View

18.

Mitsuyasu R, Merigan T, Carr A, Zack J, Winters M, Workman C . Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells. Nat Med. 2009; 15(3):285-92. PMC: 2768566. DOI: 10.1038/nm.1932. View

19.

Suzuki K, Hattori S, Marks K, Ahlenstiel C, Maeda Y, Ishida T . Promoter Targeting shRNA Suppresses HIV-1 Infection In vivo Through Transcriptional Gene Silencing. Mol Ther Nucleic Acids. 2013; 2:e137. PMC: 3894581. DOI: 10.1038/mtna.2013.64. View

20.

von Laer D, Hasselmann S, Hasselmann K . Impact of gene-modified T cells on HIV infection dynamics. J Theor Biol. 2005; 238(1):60-77. DOI: 10.1016/j.jtbi.2005.05.005. View