The Splice of Life: Does RNA Processing Have a Role in HIV-1 Persistence?

Pasternak, Alexander; Berkhout, Ben

doi:10.3390/v13091751

Cited by 16 publications

(17 citation statements)

References 101 publications

(137 reference statements)

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“…This barrier to HIV splicing could involve host factors such as spliceosomes and other transcriptional regulators ( 70 ). Additionally, proviral sequence features, such as inefficient splice acceptor sites, likely contribute to low levels of multiply spliced HIV RNA production ( 46 , 68 ). The interactome of different HIV RNAs may also contribute to splicing, stability, export, and translation differences ( 64 ).…”

Section: Discussionmentioning

confidence: 99%

Combined noncanonical NF-κB agonism and targeted BET bromodomain inhibition reverse HIV latency ex vivo

Falcinelli¹,

Peterson²,

Turner³

et al. 2022

Journal of Clinical Investigation

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Latency reversal strategies for HIV cure using inhibitor of apoptosis protein (IAP) antagonists (IAPi) induce unprecedented levels of latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting of the reservoir may require combinatorial approaches. A Jurkat latency model screen for IAPi combination partners demonstrated synergistic latency reversal with bromodomain (BD) and extraterminal domain protein inhibitors (BETi). Mechanistic investigations using CRISPR-CAS9 and single-cell RNA-Seq informed comprehensive ex vivo evaluations of IAPi plus pan-BET, bD-selective BET, or selective BET isoform targeting in CD4 + T cells from ART-suppressed donors. IAPi+BETi treatment resulted in striking induction of cell-associated HIV gag RNA, but lesser induction of fully elongated and tat-rev RNA compared with T cell activation–positive controls. IAPi+BETi resulted in HIV protein induction in bulk cultures of CD4 + T cells using an ultrasensitive p24 assay, but did not result in enhanced viral outgrowth frequency using a standard quantitative viral outgrowth assay. This study defines HIV transcriptional elongation and splicing as important barriers to latent HIV protein expression following latency reversal, delineates the roles of BET proteins and their BDs in HIV latency, and provides a rationale for exploration of IAPi+BETi in animal models of HIV latency.

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Section: Discussionmentioning

confidence: 99%

Combined noncanonical NF-κB agonism and targeted BET bromodomain inhibition reverse HIV latency ex vivo

Falcinelli¹,

Peterson²,

Turner³

et al. 2022

Journal of Clinical Investigation

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“…The HIV-1 genome encodes viral proteins in a single unspliced polycistronic transcript of 9.2 kb ( Purcell and Martin, 1993 ; Bohne et al., 2005 ; Stoltzfus, 2009 ). The HIV-1 US vRNA contains at least four 5’ splice donor sites and ten 3’ splice acceptor sites and the host cell spliceosome combines multiple splice donors and acceptors, that facilitates alternative splicing resulting in the production of over 100 HIV-1 vRNA transcripts of 4kb HIV-1 SS vRNA and 2 kb HIV-1 MS vRNA ( Purcell and Martin, 1993 ; Ocwieja et al., 2012 ; Emery et al., 2017 ; Pasternak and Berkhout, 2021 ). HIV-1 US vRNA encodes for the structural precursor proteins Gag and Gag-Pol and serves as genomic RNA.…”

Section: Co and Post-transcriptional Regulation Of Hiv-1 Gene Express...mentioning

confidence: 99%

HibeRNAtion: HIV-1 RNA Metabolism and Viral Latency

Crespo

Rao

Mahmoudi

2022

Front. Cell. Infect. Microbiol.

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HIV-1 infection remains non-curative due to the latent reservoir, primarily a small pool of resting memory CD4+ T cells bearing replication-competent provirus. Pharmacological reversal of HIV-1 latency followed by intrinsic or extrinsic cell killing has been proposed as a promising strategy to target and eliminate HIV-1 viral reservoirs. Latency reversing agents have been extensively studied for their role in reactivating HIV-1 transcription in vivo, although no permanent reduction of the viral reservoir has been observed thus far. This is partly due to the complex nature of latency, which involves strict intrinsic regulation at multiple levels at transcription and RNA processing. Still, the molecular mechanisms that control HIV-1 latency establishment and maintenance have been almost exclusively studied in the context of chromatin remodeling, transcription initiation and elongation and most known LRAs target LTR-driven transcription by manipulating these. RNA metabolism is a largely understudies but critical mechanistic step in HIV-1 gene expression and latency. In this review we provide an update on current knowledge on the role of RNA processing mechanisms in viral gene expression and latency and speculate on the possible manipulation of these pathways as a therapeutic target for future cure studies.

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“…HIV-1 latency is regulated at both transcriptional and post-transcriptional levels, as discussed in this Special Issue by Pasternak and Berkhout [ 2 ]. There appears to be a block to splicing in latently infected cells, leading to an elevated ratio of unspliced/multiply spliced HIV-1 mRNAs [ 56 ].…”

Section: Splicingmentioning

confidence: 99%

“…Furthermore, unspliced viral RNA can induce an immune response without protein expression. The unspliced/multiply spliced RNA ratio is thought to be an important biomarker [ 2 ].…”

Section: Splicingmentioning

confidence: 99%

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Retroviral RNA Processing

Beemon¹

2022

Viruses

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This review is an accompaniment to a Special Issue on “Retroviral RNA Processing”. It discusses post-transcriptional regulation of retroviruses, ranging from the ancient foamy viruses to more modern viruses, such as HIV-1, HTLV-1, Rous sarcoma virus, murine leukemia virus, mouse mammary tumor virus, and Mason-Pfizer monkey virus. This review is not comprehensive. However, it tries to address some of the major questions in the field with examples of how different retroviruses express their genes. It is amazing that a single primary RNA transcript can have so many possible fates: genomic RNA, unspliced mRNA, and up to 50 different alternatively spliced mRNAs. This review will discuss the sorting of RNAs for packaging or translation, RNA nuclear export mechanisms, splicing, translation, RNA modifications, and avoidance of nonsense-mediated RNA decay.

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The Splice of Life: Does RNA Processing Have a Role in HIV-1 Persistence?

Cited by 16 publications

References 101 publications

Combined noncanonical NF-κB agonism and targeted BET bromodomain inhibition reverse HIV latency ex vivo

Combined noncanonical NF-κB agonism and targeted BET bromodomain inhibition reverse HIV latency ex vivo

HibeRNAtion: HIV-1 RNA Metabolism and Viral Latency

Retroviral RNA Processing

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