HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells

Reuschl, Ann-Kathrin; Mesner, Dejan; Shivkumar, Maitreyi; Whelan, Matthew; Pallett, Laura J.; Guerra-Assunção, José Afonso; Madansein, Rajhmun; Dullabh, Kaylesh J; Sigal, Alex; Thornhill, John; Herrera, Carolina; Fidler, Sarah; Noursadeghi, Mahdad; Maini, Mala K.; Jolly, Clare

doi:10.1016/j.celrep.2022.110650

Cited by 14 publications

(7 citation statements)

References 76 publications

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“…Their work identified that viral spread within lymphocyte populations via cell-to-cell contacts preferentially leads to infection of resting memory T cells. In this scenario, virion-delivered Vpr induces the establishment of a tissue-resident phenotype by synergizing with IL-7 to activate STAT5, ultimately inducing a virus-favorable transcriptional program [ 97 ]. Ectopic STAT5 activation has recently been observed to alter the epigenome of CD4 + T cells and push their phenotype towards polyfunctionality, although such an alteration may present yet unidentified implications in the context of infection, perhaps playing a significant role in HIV pathogenesis [ 98 ].…”

Section: Systems-level Manipulation Of the Host Cellmentioning

confidence: 99%

“…In summary, the evidence gathered in a physiologically relevant context indicates that Vpr induces an early uptick in ISG transcription upon infection [ 81 ] and indirectly enables cap hypermethylation, allowing viral mRNAs to overcome the host’s transcriptional blockage [ 92 , 93 , 94 ]. It has also been shown that Vpr plays a leading role in manipulating IL-7 and STAT5 immune signaling, prompting the establishment of latency with the help of the host lymphocyte’s cellular environment [ 97 ]. In addition, the CRL4-DDB1-DCAF1-mediated remodeling of the host proteome not only factually explains many of the alterations reported in this cell population but also confirms that Vpr actively targets the HR-related proteins MUS81 and EME1 for degradation, endorsing a branch of the hypothesis that attributes Vpr to the DNA damage response pathway [ 101 ].…”

Section: Systems-level Manipulation Of the Host Cellmentioning

confidence: 99%

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HIV-1 Vpr Functions in Primary CD4+ T Cells

Vanegas-Torres,

Schindler

2024

Viruses

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HIV-1 encodes four accesory proteins in addition to its structural and regulatory genes. Uniquely amongst them, Vpr is abundantly present within virions, meaning it is poised to exert various biological effects on the host cell upon delivery. In this way, Vpr contributes towards the establishment of a successful infection, as evidenced by the extent to which HIV-1 depends on this factor to achieve full pathogenicity in vivo. Although HIV infects various cell types in the host organism, CD4+ T cells are preferentially targeted since they are highly permissive towards productive infection, concomitantly bringing about the hallmark immune dysfunction that accompanies HIV-1 spread. The last several decades have seen unprecedented progress in unraveling the activities Vpr possesses in the host cell at the molecular scale, increasingly underscoring the importance of this viral component. Nevertheless, it remains controversial whether some of these advances bear in vivo relevance, since commonly employed cellular models significantly differ from primary T lymphocytes. One prominent example is the “established” ability of Vpr to induce G2 cell cycle arrest, with enigmatic physiological relevance in infected primary T lymphocytes. The objective of this review is to present these discoveries in their biological context to illustrate the mechanisms whereby Vpr supports HIV-1 infection in CD4+ T cells, whilst identifying findings that require validation in physiologically relevant models.

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Section: Systems-level Manipulation Of the Host Cellmentioning

confidence: 99%

Section: Systems-level Manipulation Of the Host Cellmentioning

confidence: 99%

HIV-1 Vpr Functions in Primary CD4+ T Cells

Vanegas-Torres,

Schindler

2024

Viruses

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“…This should be taken into consideration when delivering Cas RNP using the Vpr mechanism. On the other hand, Reuschl and coauthors recently showed that Vpr in the context of HIV reprograms naïve infected T cells to tissue-resident memory phenotype cells [ 53 ]. This phenotype is known to be more resistant to apoptotic signals, meaning that the survival of edited primary human lymphocytes may not be affected by Vpr.…”

Section: Retroviral Disassembly and Cell Transduction Efficiency With...mentioning

confidence: 99%

Packaging and Uncoating of CRISPR/Cas Ribonucleoproteins for Efficient Gene Editing with Viral and Non-Viral Extracellular Nanoparticles

Mazurov

Ramadan

Kruglova

2023

Viruses

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Rapid progress in gene editing based on clustered regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas) has revolutionized functional genomic studies and genetic disease correction. While numerous gene editing applications have been easily adapted by experimental science, the clinical utility of CRISPR/Cas remains very limited due to difficulty in delivery to primary cells and possible off-target effects. The use of CRISPR in the form of a ribonucleoprotein (RNP) complex substantially reduces the time of DNA exposure to the effector nuclease and minimizes its off-target activity. The traditional electroporation and lipofection methods lack the cell-type specificity of RNP delivery, can be toxic for cells, and are less efficient when compared to nanoparticle transporters. This review focuses on CRISPR/Cas RNP packaging and delivery using retro/lentiviral particles and exosomes. First, we briefly describe the natural stages of viral and exosomal particle formation, release and entry into the target cells. This helps us understand the mechanisms of CRISPR/Cas RNP packaging and uncoating utilized by the current delivery systems, which we discuss afterward. Much attention is given to the exosomes released during viral particle production that can be passively loaded with RNPs as well as the mechanisms necessary for particle fusion, RNP release, and transportation inside the target cells. Collectively, together with specific packaging mechanisms, all these factors can substantially influence the editing efficiency of the system. Finally, we discuss ways to improve CRISPR/Cas RNP delivery using extracellular nanoparticles.

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“…The HIV-1 clone pNL4.3 was obtained from the CFAR, NIBSC (cat# 2006) and virus stocks prepared as described previously 67 . NL4.3 stocks were produced by plasmid transfection of HEK 293T cells with Fugene 6 (Promega).…”

Section: Production Of Hiv-1 Nl43mentioning

confidence: 99%

Synthetic PROTACs based on a depsipeptide macrocycle selectively degrade cyclophilin A and inhibit HIV-1

Gathmann

Newton

Ridewood

et al. 2023

Preprint

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We have designed and characterised PROteolysis TArgeting Chimeras (PROTACs) active against the human protein cyclophilin A (CypA), a viral cofactor required for efficient replication of a series of unrelated viruses. Our cyclophilin PROTACs have fully synthetic macrocycle warheads derived from Sanglifehrin A, which are structurally different from the classical Cyp inhibitor, cyclosporin A, and do not have immunosuppressive activity. They effectively degrade CypA, with selectivity over CypB, in a ubiquitin dependent manner and across a variety of cell lines and primary cells. Critically, CypA degradation underlies improved antiviral activity against HIV-1 in primary T cells compared to the non-PROTAC parental inhibitor. We propose that PROTACs targeting CypA to inhibit viral replication promise high antiviral potency, reduced evolution of viral resistance, and broad specificity for unrelated viruses.

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HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells

Cited by 14 publications

References 76 publications

HIV-1 Vpr Functions in Primary CD4+ T Cells

HIV-1 Vpr Functions in Primary CD4+ T Cells

Packaging and Uncoating of CRISPR/Cas Ribonucleoproteins for Efficient Gene Editing with Viral and Non-Viral Extracellular Nanoparticles

Synthetic PROTACs based on a depsipeptide macrocycle selectively degrade cyclophilin A and inhibit HIV-1

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