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To date, the only intervention that has cured HIV infection has been bone marrow transplants from HIV-resistant donors to HIV-infected recipients. This approach has been used to both cure hematological malignancies and HIV infection, but it cannot be widely adopted due to the high risk of mortality associated with cell transplants between individuals. To overcome this limitation, several approaches have been developed to generate HIV resistance using gene therapy in an infected individual's own cells. With the growing arsenal of effective methods to generate HIV-resistant cells, a safe and effective combination gene therapy approach to cure HIV infection is fast approaching. Here, we review several gene therapy-based methods to generate HIV-resistant cells including the expression of antiviral genes, genome editing, and transcriptional gene silencing. Their varied mechanisms, advantages, and disadvantages are discussed, and perspectives are provided for how they may be combined to design an effective gene therapy for HIV.

Current drug therapies for human immunodeficiency virus type 1 (HIV) infection are effective in preventing progression to acquired immune deficiency syndrome but do not eliminate the infection and are associated with unwanted side effects. A potential alternative is to modify the genome of patient cells via gene therapy to confer HIV resistance to these cells. Small RNAs are the largest and most diverse group of anti-HIV genes that have been developed for engineering HIV resistant cells. In this review, we summarize progress on the three major classes of anti-HIV RNAs including short hairpin RNAs that use the RNA interference pathway, RNA decoys and aptamers that bind specifically to a protein or RNA as well as ribozymes that mediate cleavage of specific targets. We also review methods used for the delivery of these genes into the genome of patient cells and provide some perspectives on the future of small RNAs in HIV therapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)