Abstract
C-C chemokine receptor type 5 (CCR5) is utilized by human immunodeficiency virus (HIV) as a co-receptor for cell entry. Suppression of the CCR5 gene by artificial microRNAs (amiRNAs) could confer cell resistance. In previous work, we created a lentivector that encoded the polycistron of two identical amiRNAs that could effectively suppress CCR5. However, tandem repeats in lentiviral vectors led to deletions of the repeated sequences during reverse transcription of the vector RNA. To solve this problem, we have created a new amiRNA against CCR5, mic1002, which has a different microRNA scaffold and targets a different sequence. Replacing one of the two identical tandem amiRNAs in the polycistron with the mic1002 amiRNA increased the accuracy of its lentiviral vector transfer while retaining its ability to effectively suppress CCR5. A lentiviral vector containing two heterogenic amiRNAs significantly inhibited HIV replication in a vector-transduced human CD4+ lymphocyte culture.
Highlights
The spread of human immunodeficiency virus (HIV) infection is of great concern worldwide.Antiretroviral drugs, which HIV patients must take for their entire lives, can be toxic and do not always prevent disease progression due to the emergence of resistant HIV strains
We previously developed several lentiviral constructs encoding anti-chemokine receptor type 5 (CCR5) artificial microRNAs (amiRNAs)
HT1080 CCR5-EGFP cells [17] were cultured in Minimum Essential Medium supplemented with 10% FBS
Summary
The spread of human immunodeficiency virus (HIV) infection is of great concern worldwide.Antiretroviral drugs, which HIV patients must take for their entire lives, can be toxic and do not always prevent disease progression due to the emergence of resistant HIV strains. The spread of human immunodeficiency virus (HIV) infection is of great concern worldwide. New treatment approaches are being sought, including a gene therapy-based approach involving the genetic modification of cells susceptible to HIV to promote their viral resistance. This could lead to long-term infection control without chemotherapy or even to a complete cure. A promising strategy for HIV gene therapy is downregulating the expression of CCR5, one of two co-receptors for viral cell entry [1]. The genetic deficiency of CCR5 in individuals bearing mutant alleles confers resistance to HIV infection, while people lacking CCR5 seem perfectly healthy [2,3,4,5]
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