Reversal of Epigenetic Silencing Allows Robust HIV-1 Replication in the Absence of Integrase Function

ABSTRACT Integration of the proviral DNA intermediate into the host cell genome normally represents an essential step in the retroviral life cycle. While the reason(s) for this requirement remains unclear, it is known that unintegrated proviral DNA is epigenetically silenced. Here, we demonstrate th...

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Autores principales:	Ishak D. Irwan, Heather L. Karnowski, Hal P. Bogerd, Kevin Tsai, Bryan R. Cullen
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	HIV-1 HTLV-1 Tax integrase cccDNA integrase inhibitors Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e89049ba44c846f8b00d93509c7f0941
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spelling	oai:doaj.org-article:e89049ba44c846f8b00d93509c7f09412021-11-15T15:56:46ZReversal of Epigenetic Silencing Allows Robust HIV-1 Replication in the Absence of Integrase Function10.1128/mBio.01038-202150-7511https://doaj.org/article/e89049ba44c846f8b00d93509c7f09412020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01038-20https://doaj.org/toc/2150-7511ABSTRACT Integration of the proviral DNA intermediate into the host cell genome normally represents an essential step in the retroviral life cycle. While the reason(s) for this requirement remains unclear, it is known that unintegrated proviral DNA is epigenetically silenced. Here, we demonstrate that human immunodeficiency virus 1 (HIV-1) mutants lacking a functional integrase (IN) can mount a robust, spreading infection in cells expressing the Tax transcription factor encoded by human T-cell leukemia virus 1 (HTLV-1). In these cells, HIV-1 forms episomal DNA circles, analogous to hepatitis B virus (HBV) covalently closed circular DNAs (cccDNAs), that are transcriptionally active and fully capable of supporting viral replication. In the presence of Tax, induced NF-κB proteins are recruited to the long terminal repeat (LTR) promoters present on unintegrated HIV-1 DNA, and this recruitment in turn correlates with the loss of inhibitory epigenetic marks and the acquisition of activating marks on histones bound to viral DNA. Therefore, HIV-1 is capable of replication in the absence of integrase function if the epigenetic silencing of unintegrated viral DNA can be prevented or reversed. IMPORTANCE While retroviral DNA is synthesized normally after infection by integrase-deficient viruses, the resultant episomal DNA is then epigenetically silenced. Here, we show that expression of the Tax transcription factor encoded by a second human retrovirus, HTLV-1, prevents or reverses the epigenetic silencing of unintegrated HIV-1 DNA and instead induces the addition of activating epigenetic marks and the recruitment of NF-κB/Rel proteins to the HIV-1 LTR promoter. Moreover, in the presence of Tax, the HIV-1 DNA circles that form in the absence of integrase function are not only efficiently transcribed but also support a spreading, pathogenic integrase-deficient (IN−) HIV-1 infection. Thus, retroviruses have the potential to replicate without integration, as is indeed seen with HBV. Moreover, these data suggest that integrase inhibitors may be less effective in the treatment of HIV-1 infections in individuals who are also coinfected with HTLV-1.Ishak D. IrwanHeather L. KarnowskiHal P. BogerdKevin TsaiBryan R. CullenAmerican Society for MicrobiologyarticleHIV-1HTLV-1TaxintegrasecccDNAintegrase inhibitorsMicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	HIV-1 HTLV-1 Tax integrase cccDNA integrase inhibitors Microbiology QR1-502
spellingShingle	HIV-1 HTLV-1 Tax integrase cccDNA integrase inhibitors Microbiology QR1-502 Ishak D. Irwan Heather L. Karnowski Hal P. Bogerd Kevin Tsai Bryan R. Cullen Reversal of Epigenetic Silencing Allows Robust HIV-1 Replication in the Absence of Integrase Function
description	ABSTRACT Integration of the proviral DNA intermediate into the host cell genome normally represents an essential step in the retroviral life cycle. While the reason(s) for this requirement remains unclear, it is known that unintegrated proviral DNA is epigenetically silenced. Here, we demonstrate that human immunodeficiency virus 1 (HIV-1) mutants lacking a functional integrase (IN) can mount a robust, spreading infection in cells expressing the Tax transcription factor encoded by human T-cell leukemia virus 1 (HTLV-1). In these cells, HIV-1 forms episomal DNA circles, analogous to hepatitis B virus (HBV) covalently closed circular DNAs (cccDNAs), that are transcriptionally active and fully capable of supporting viral replication. In the presence of Tax, induced NF-κB proteins are recruited to the long terminal repeat (LTR) promoters present on unintegrated HIV-1 DNA, and this recruitment in turn correlates with the loss of inhibitory epigenetic marks and the acquisition of activating marks on histones bound to viral DNA. Therefore, HIV-1 is capable of replication in the absence of integrase function if the epigenetic silencing of unintegrated viral DNA can be prevented or reversed. IMPORTANCE While retroviral DNA is synthesized normally after infection by integrase-deficient viruses, the resultant episomal DNA is then epigenetically silenced. Here, we show that expression of the Tax transcription factor encoded by a second human retrovirus, HTLV-1, prevents or reverses the epigenetic silencing of unintegrated HIV-1 DNA and instead induces the addition of activating epigenetic marks and the recruitment of NF-κB/Rel proteins to the HIV-1 LTR promoter. Moreover, in the presence of Tax, the HIV-1 DNA circles that form in the absence of integrase function are not only efficiently transcribed but also support a spreading, pathogenic integrase-deficient (IN−) HIV-1 infection. Thus, retroviruses have the potential to replicate without integration, as is indeed seen with HBV. Moreover, these data suggest that integrase inhibitors may be less effective in the treatment of HIV-1 infections in individuals who are also coinfected with HTLV-1.
format	article
author	Ishak D. Irwan Heather L. Karnowski Hal P. Bogerd Kevin Tsai Bryan R. Cullen
author_facet	Ishak D. Irwan Heather L. Karnowski Hal P. Bogerd Kevin Tsai Bryan R. Cullen
author_sort	Ishak D. Irwan
title	Reversal of Epigenetic Silencing Allows Robust HIV-1 Replication in the Absence of Integrase Function
title_short	Reversal of Epigenetic Silencing Allows Robust HIV-1 Replication in the Absence of Integrase Function
title_full	Reversal of Epigenetic Silencing Allows Robust HIV-1 Replication in the Absence of Integrase Function
title_fullStr	Reversal of Epigenetic Silencing Allows Robust HIV-1 Replication in the Absence of Integrase Function
title_full_unstemmed	Reversal of Epigenetic Silencing Allows Robust HIV-1 Replication in the Absence of Integrase Function
title_sort	reversal of epigenetic silencing allows robust hiv-1 replication in the absence of integrase function
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/e89049ba44c846f8b00d93509c7f0941
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Reversal of Epigenetic Silencing Allows Robust HIV-1 Replication in the Absence of Integrase Function

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