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HIV Preintegration Transcription and Host Antagonism

Retrovirus integration is an obligatory step for the viral life cycle, but large amounts of unintegrated DNA (uDNA) accumulate during retroviral infection. For simple retroviruses, in the absence of integration, viral genomes are epigenetically silenced in host cells. For complex retroviruses such a...

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Autor principal: Wu, Yuntao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Bentham Science Publishers 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10661980/
https://www.ncbi.nlm.nih.gov/pubmed/37345240
http://dx.doi.org/10.2174/1570162X21666230621122637
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author Wu, Yuntao
author_facet Wu, Yuntao
author_sort Wu, Yuntao
collection PubMed
description Retrovirus integration is an obligatory step for the viral life cycle, but large amounts of unintegrated DNA (uDNA) accumulate during retroviral infection. For simple retroviruses, in the absence of integration, viral genomes are epigenetically silenced in host cells. For complex retroviruses such as HIV, preintegration transcription has been found to occur at low levels from a large population of uDNA even in the presence of host epigenetic silencing mechanisms. HIV preintegration transcription has been suggested to be a normal early process of HIV infection that leads to the syntheses of all three classes of viral transcripts: multiply-spliced, singly-spliced, and unspliced genomic RNA; only viral early proteins such as Nef are selectively translated at low levels in blood CD4 T cells and macrophages, the primary targets of HIV. The initiation and persistence of HIV preintegration transcription have been suggested to rely on viral accessory proteins, particularly virion Vpr and de novo Tat generated from uDNA; both proteins have been shown to antagonize host epigenetic silencing of uDNA. In addition, stimulation of latently infected resting T cells and macrophages with cytokines, PKC activator, or histone deacetylase inhibitors has been found to greatly upregulate preintegration transcription, leading to low-level viral production or even replication from uDNA. Functionally, Nef synthesized from preintegration transcription is biologically active in modulating host immune functions, lowering the threshold of T cell activation, and downregulating surface CD4, CXCR4/CCR5, and HMC receptors. The early Tat activity from preintegration transcription antagonizes repressive minichromatin assembled onto uDNA. The study of HIV preintegration transcription is important to understanding virus-host interaction and antagonism, viral persistence, and the mechanism of integrase drug resistance. The application of unintegrated lentiviral vectors for gene therapy also offers a safety advantage for minimizing retroviral vector-mediated insertional mutagenesis.
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spelling pubmed-106619802023-11-21 HIV Preintegration Transcription and Host Antagonism Wu, Yuntao Curr HIV Res Medicine, Anti-Infectives and Infectious Diseases, Immunology, Virology Retrovirus integration is an obligatory step for the viral life cycle, but large amounts of unintegrated DNA (uDNA) accumulate during retroviral infection. For simple retroviruses, in the absence of integration, viral genomes are epigenetically silenced in host cells. For complex retroviruses such as HIV, preintegration transcription has been found to occur at low levels from a large population of uDNA even in the presence of host epigenetic silencing mechanisms. HIV preintegration transcription has been suggested to be a normal early process of HIV infection that leads to the syntheses of all three classes of viral transcripts: multiply-spliced, singly-spliced, and unspliced genomic RNA; only viral early proteins such as Nef are selectively translated at low levels in blood CD4 T cells and macrophages, the primary targets of HIV. The initiation and persistence of HIV preintegration transcription have been suggested to rely on viral accessory proteins, particularly virion Vpr and de novo Tat generated from uDNA; both proteins have been shown to antagonize host epigenetic silencing of uDNA. In addition, stimulation of latently infected resting T cells and macrophages with cytokines, PKC activator, or histone deacetylase inhibitors has been found to greatly upregulate preintegration transcription, leading to low-level viral production or even replication from uDNA. Functionally, Nef synthesized from preintegration transcription is biologically active in modulating host immune functions, lowering the threshold of T cell activation, and downregulating surface CD4, CXCR4/CCR5, and HMC receptors. The early Tat activity from preintegration transcription antagonizes repressive minichromatin assembled onto uDNA. The study of HIV preintegration transcription is important to understanding virus-host interaction and antagonism, viral persistence, and the mechanism of integrase drug resistance. The application of unintegrated lentiviral vectors for gene therapy also offers a safety advantage for minimizing retroviral vector-mediated insertional mutagenesis. Bentham Science Publishers 2023-09-05 2023-09-05 /pmc/articles/PMC10661980/ /pubmed/37345240 http://dx.doi.org/10.2174/1570162X21666230621122637 Text en © 2023 Bentham Science Publishers https://creativecommons.org/licenses/by/4.0/© 2023 The Author(s). Published by Bentham Science Publisher. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode)
spellingShingle Medicine, Anti-Infectives and Infectious Diseases, Immunology, Virology
Wu, Yuntao
HIV Preintegration Transcription and Host Antagonism
title HIV Preintegration Transcription and Host Antagonism
title_full HIV Preintegration Transcription and Host Antagonism
title_fullStr HIV Preintegration Transcription and Host Antagonism
title_full_unstemmed HIV Preintegration Transcription and Host Antagonism
title_short HIV Preintegration Transcription and Host Antagonism
title_sort hiv preintegration transcription and host antagonism
topic Medicine, Anti-Infectives and Infectious Diseases, Immunology, Virology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10661980/
https://www.ncbi.nlm.nih.gov/pubmed/37345240
http://dx.doi.org/10.2174/1570162X21666230621122637
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