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Can the HIV-1 splicing machinery be targeted for drug discovery?

Authors Dlamini Z, Hull R

Received 24 August 2016

Accepted for publication 27 November 2016

Published 10 March 2017 Volume 2017:9 Pages 63—75


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Professor Bassel Sawaya

Zodwa Dlamini, Rodney Hull

Research, Innovation & Engagements Portfolio, Mangosuthu University of Technology, Durban, South Africa

Abstract: HIV-1 is able to express multiple protein types and isoforms from a single 9 kb mRNA transcript. These proteins are also expressed at particular stages of viral development, and this is achieved through the control of alternative splicing and the export of these transcripts from the nucleus. The nuclear export is controlled by the HIV protein Rev being required to transport incompletely spliced and partially spliced mRNA from the nucleus where they are normally retained. This implies a close relationship between the control of alternate splicing and the nuclear export of mRNA in the control of HIV-1 viral proliferation. This review discusses both the processes. The specificity and regulation of splicing in HIV-1 is controlled by the use of specific splice sites as well as exonic splicing enhancer and exonic splicing silencer sequences. The use of these silencer and enhancer sequences is dependent on the serine arginine family of proteins as well as the heterogeneous nuclear ribonucleoprotein family of proteins that bind to these sequences and increase or decrease splicing. Since alternative splicing is such a critical factor in viral development, it presents itself as a promising drug target. This review aims to discuss the inhibition of splicing, which would stall viral development, as an anti-HIV therapeutic strategy. In this review, the most recent knowledge of splicing in human immunodeficiency viral development and the latest therapeutic strategies targeting human immunodeficiency viral splicing are discussed.

Keywords: alternative splicing, exonic splicing enhancer, exonic specific silencer, splicing based therapies, SR proteins, hnRNP, Rev, Tat, Vpr

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