title: Engineered lentiviral vectors pseudotyped with a CD4 receptor and a fusogenic protein can target cells expressing HIV-1 envelope proteins.
abstract: Lentiviral vectors (LVs) derived from human immunodeficiency virus type 1 (HIV-1) are promising vehicles for gene delivery because they not only efficiently transduce both dividing and non-dividing cells, but also maintain long-term transgene expression. Development of an LV system capable of transducing cells in a cell type-specific manner can be beneficial for certain applications that rely on targeted gene delivery. Previously it was shown that an inverse fusion strategy that incorporated an HIV-1 receptor (CD4) and its co-receptor (CXCR4 or CCR5) onto vector surfaces could confer to LVs the ability to selectively deliver genes to HIV-1 envelope-expressing cells. To build upon this work, we aim to improve its relatively low transduction efficiency and circumvent its inability to target multiple tropisms of HIV-1 by a single vector. We investigated a method to create LVs co-enveloped with the HIV-1 cellular receptor CD4 and a fusogenic protein derived from the Sindbis virus glycoprotein and tested its efficiency to selectively deliver genes into cells expressing HIV-1 envelope proteins. The engineered LV system yields a higher level of transduction efficiency and a broader tropism towards cells displaying the HIV-1 envelope protein (Env) than the previously developed system. Furthermore, we demonstrated in vitro that this engineered LV can preferentially deliver suicide gene therapy to HIV-1 envelope-expressing cells. We conclude that it is potentially feasible to target LVs towards HIV-1-infected cells by functional co-incorporation of the CD4 and fusogenic proteins, and provide preliminary evidence for further investigation on a potential alternative treatment for eradicating HIV-1-infected cells that produce drug-resistant viruses after highly active antiretroviral therapy (HAART).
authors.affiliation: Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA 90089, United States.
authors.forename: Chi-Lin
authors.initials: CL
authors.lastname: Lee
authors.forename: Jason
authors.initials: J
authors.lastname: Dang
authors.forename: Kye-Il
authors.initials: KI
authors.lastname: Joo
authors.forename: Pin
authors.initials: P
authors.lastname: Wang
mesh_terms: D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D015728:Receptors, HIV / Q000235:genetics / Q000378:metabolism*; D012845:Sindbis Virus / Q000235:genetics; D014161:Transduction, Genetic; D014760:Viral Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D053585:Virus Attachment; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D015728:Receptors, HIV; D014760:Viral Fusion Proteins; D054299:env Gene Products, Human Immunodeficiency Virus