Let It Go: HIV-1
            <i>cis</i>
            -Acting Repressive Sequences

Ostermann, Philipp Niklas; Ritchie, Anastasia; Ptok, Johannes; Schaal, Heiner

doi:10.1128/jvi.00342-21

Cited by 8 publications

(9 citation statements)

References 131 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Low levels of Rev proteins in latently infected cells that transport unspliced HIV RNAs out of the nucleus may explain this finding ( 57 ). Another possible contributor is proviruses with deletions and/or mutations in cis-acting repressive sequences, which normally function to facilitate nuclear retention of unspliced HIV RNAs ( 58 , 59 ). An alternative explanation for this phenomenon is Rev-independent export of unspliced HIV gag transcripts.…”

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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…It is important to note that the RRE-Rev functions to increase transcript stability and transport, as well as to rescue HIV-1 mRNA from splicing. In the HIV-1 mRNA messages in which splicing sites are absent, enhancement of mRNA transport from the nucleus, mediated through RRE-Rev interaction, is related to reducing the impact of negative Cis-regulatory RNA elements (CREs) in the HIV-1 mRNA [ 48 ]. Codon optimization destroys nine of these putative negative CREs in the EnvA74-EC coding region/mRNA, suggesting this “codon-optimized” HIV-1 mRNA may be more related to destroying the CREs and possibly eliminating the need of Rev-RRE interactions.…”

Section: Resultsmentioning

confidence: 99%

Optimal Expression, Function, and Immunogenicity of an HIV-1 Vaccine Derived from the Approved Ebola Vaccine, rVSV-ZEBOV

Azizi

Knapp

et al. 2023

Vaccines

View full text Add to dashboard Cite

Vesicular stomatitis virus (VSV) remains an attractive platform for a potential HIV-1 vaccine but hurdles remain, such as selection of a highly immunogenic HIV-1 Envelope (Env) with a maximal surface expression on recombinant rVSV particles. An HIV-1 Env chimera with the transmembrane domain (TM) and cytoplasmic tail (CT) of SIVMac239 results in high expression on the approved Ebola vaccine, rVSV-ZEBOV, also harboring the Ebola Virus (EBOV) glycoprotein (GP). Codon-optimized (CO) Env chimeras derived from a subtype A primary isolate (A74) are capable of entering a CD4+/CCR5+ cell line, inhibited by HIV-1 neutralizing antibodies PGT121, VRC01, and the drug, Maraviroc. The immunization of mice with the rVSV-ZEBOV carrying the CO A74 Env chimeras results in anti-Env antibody levels as well as neutralizing antibodies 200-fold higher than with the NL4-3 Env-based construct. The novel, functional, and immunogenic chimeras of CO A74 Env with the SIV_Env-TMCT within the rVSV-ZEBOV vaccine are now being tested in non-human primates.

show abstract

“…Cis-acting repressing sequence (CRS) is a type of RNA sequence element that regulates gene expression by inhibiting the nuclear export of mRNAs ( 41 ). It is widely present in a variety of viruses, including HIV-1 ( 42 – 44 ), EIAV ( 45 ), HBV ( 46 ), and HPV ( 47 ), as well as in cellular transcripts.…”

Section: Discussionmentioning

confidence: 99%

A Novel, Fully Spliced, Accessory Gene in Equine Lentivirus with Distinct Rev-Responsive Element

Zhang

et al. 2022

J Virol

View full text Add to dashboard Cite

show abstract

Let It Go: HIV-1 cis -Acting Repressive Sequences

Cited by 8 publications

References 131 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

Optimal Expression, Function, and Immunogenicity of an HIV-1 Vaccine Derived from the Approved Ebola Vaccine, rVSV-ZEBOV

A Novel, Fully Spliced, Accessory Gene in Equine Lentivirus with Distinct Rev-Responsive Element

Contact Info

Product

Resources

About