HIV-1 Natural Antisense Transcription and Its Role in Viral Persistence

Li, Rui; Sklutuis, Rachel; Groebner, Jennifer L.; Romerio, Fabio

doi:10.3390/v13050795

Cited by 11 publications

(10 citation statements)

References 207 publications

(351 reference statements)

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“…Initial evidence from acutely and chronically infected cell lines was later extended to PBMC from early-stage, asymptomatic patients [ 30 , 31 ]. Indeed, antisense transcription appears to be a feature of many human and animal retroviruses [ 32 ]. Our group has independently confirmed the expression of HIV-1 antisense transcripts in multiple cell systems, including in chronically infected cell lines, acutely infected primary human CD4+ T cells, and resting CD4+ T cells isolated from peripheral blood of ART-suppressed HIV-1 [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic Regulation of HIV-1 Sense and Antisense Transcription in Response to Latency-Reversing Agents

Caico

Zhang

et al. 2023

ncRNA

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Nucleosomes positioned on the HIV-1 5′ long terminal repeat (LTR) regulate sense transcription as well as the establishment and maintenance of latency. A negative-sense promoter (NSP) in the 3′ LTR expresses antisense transcripts with coding and non-coding activities. Previous studies identified cis-acting elements that modulate NSP activity. Here, we used the two chronically infected T cell lines, ACH-2 and J1.1, to investigate epigenetic regulation of NSP activity. We found that histones H3 and H4 are present on the 3′ LTR in both cell lines. Following treatment with histone deacetylase inhibitors (HDACi), the levels of H3K27Ac increased and histone occupancy declined. HDACi treatment also led to increased levels of RNA polymerase II (RNPII) at NSP, and antisense transcription was induced with similar kinetics and to a similar extent as 5′ LTR-driven sense transcription. We also detected H3K9me2 and H3K27me3 on NSP, along with the enzymes responsible for these epigenetic marks, namely G9a and EZH2, respectively. Treatment with their respective inhibitors had little or no effect on RNPII occupancy at the two LTRs, but it induced both sense and antisense transcription. Moreover, the increased expression of antisense transcripts in response to treatment with a panel of eleven latency-reversing agents closely paralleled and was often greater than the effect on sense transcripts. Thus, HIV-1 sense and antisense RNA expression are both regulated via acetylation and methylation of lysine 9 and 27 on histone H3. Since HIV-1 antisense transcripts act as non-coding RNAs promoting epigenetic silencing of the 5′ LTR, our results suggest that the limited efficacy of latency-reversing agents in the context of ‘shock and kill’ cure strategies may be due to concurrent induction of antisense transcripts thwarting their effect on sense transcription.

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Section: Introductionmentioning

confidence: 99%

“…HIV-1 antisense transcripts are bifunctional RNAs with both coding and non-coding activities [ 32 ]. They contain an open reading frame encoding for an antisense protein (ASP) of ~190 amino acids with no known homologs and still unknown function.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Regulation of HIV-1 Sense and Antisense Transcription in Response to Latency-Reversing Agents

Caico

Zhang

et al. 2023

ncRNA

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“…Like HTLV-1 and HTLV-2, the HIV-1 antisense transcript also initiates in the 3′ LTR from a TATA-less promoter that functions independently of the viral transcriptional activator Tat. Several different groups have identified multiple transcriptional start sites with variable transcript length for asp (Li et al, 2021), however each transcript encodes for a functional protein called ASP. Similar to HTLV-1 hbz transcript, the HIV-1 3′ LTR produces an asp transcript with a poor polyadenylation site and therefore the transcript is predominantly nuclear (Ma et al, 2021b).…”

Section: Antisense Transcription In Human Immunodeficiency Virus Type Imentioning

confidence: 99%

Novel perspectives on antisense transcription in HIV-1, HTLV-1, and HTLV-2

et al. 2022

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The genome of retroviruses contains two promoter elements (called long terminal repeat or LTR) at the 5′ and 3′ end of their genome. Although the expression of retroviral genes generally depends on the promoter located in the 5′ LTR, the 3′ LTR also has promoter activity responsible for producing antisense transcripts. These natural antisense transcripts (NATs) are a class of RNA molecules transcribed from the opposite strand of a protein-coding gene. NATs have been identified in many prokaryotic and eukaryotic systems, as well as in human retroviruses such as human immunodeficiency virus type 1 (HIV-1) and HTLV-1/2 (human T-cell leukemia virus type 1/2). The antisense transcripts of HIV-1, HTLV-1, and HTLV-2 have been briefly characterized over the past several years. However, a complete appreciation of the role these transcripts play in the virus lifecycle and the cellular factors which regulate their transcription is still lacking. This review provides an overview of antisense transcription in human retroviruses with a specific focus on the MEF-2 family of transcription factors, the function(s) of the antisense protein products, and the application of antisense transcription models in therapeutics against HIV-1 and HTLV-1 in the context of co-infection.

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“…Importantly, antisense transcription was preferentially activated in primary monocyte-derived cells [72,73]. Thus, there is strong experimental evidence for expression of antisense mRNA transcripts in the course of HIV-1 infection of susceptible cells [54], and such transcripts may play a role in virus persistence [83].…”

Section: Formulation Of the Hypothesis For An Hiv-1 Antisense Proteinmentioning

confidence: 99%

Retroviral Antisense Transcripts and Genes: 33 Years after First Predicted, a Silent Retroviral Revolution?

Miller

Zimmer

Moutot

et al. 2021

Viruses

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Paradigm shifts throughout the history of microbiology have typically been ignored, or met with skepticism and resistance, by the scientific community. This has been especially true in the field of virology, where the discovery of a “contagium vivum fluidum”, or infectious fluid remaining after excluding bacteria by filtration, was initially ignored because it did not coincide with the established view of microorganisms. Subsequent studies on such infectious agents, eventually termed “viruses”, were met with skepticism. However, after an abundance of proof accumulated, viruses were eventually acknowledged as defined microbiological entities. Next, the proposed role of viruses in oncogenesis in animals was disputed, as was the unique mechanism of genome replication by reverse transcription of RNA by the retroviruses. This same pattern of skepticism holds true for the prediction of the existence of retroviral “antisense” transcripts and genes. From the time of their discovery, it was thought that retroviruses encoded proteins on only one strand of proviral DNA. However, in 1988, it was predicted that human immunodeficiency virus type 1 (HIV-1), and other retroviruses, express an antisense protein encoded on the DNA strand opposite that encoding the known viral proteins. Confirmation came quickly with the characterization of the antisense protein, HBZ, of the human T-cell leukemia virus type 1 (HTLV-1), and the finding that both the protein and its antisense mRNA transcript play key roles in viral replication and pathogenesis. However, acceptance of the existence, and potential importance, of a corresponding antisense transcript and protein (ASP) in HIV-1 infection and pathogenesis has lagged, despite gradually accumulating theoretical and experimental evidence. The most striking theoretical evidence is the finding that asp is highly conserved in group M viruses and correlates exclusively with subtypes, or clades, responsible for the AIDS pandemic. This review outlines the history of the major shifts in thought pertaining to the nature and characteristics of viruses, and in particular retroviruses, and details the development of the hypothesis that retroviral antisense transcripts and genes exist. We conclude that there is a need to accelerate studies on ASP, and its transcript(s), with the view that both may be important, and overlooked, targets in anti-HIV therapeutic and vaccine strategies.

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HIV-1 Natural Antisense Transcription and Its Role in Viral Persistence

Cited by 11 publications

References 207 publications

Epigenetic Regulation of HIV-1 Sense and Antisense Transcription in Response to Latency-Reversing Agents

Epigenetic Regulation of HIV-1 Sense and Antisense Transcription in Response to Latency-Reversing Agents

Novel perspectives on antisense transcription in HIV-1, HTLV-1, and HTLV-2

Retroviral Antisense Transcripts and Genes: 33 Years after First Predicted, a Silent Retroviral Revolution?

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