HIV-1 Vpr induces ciTRAN to prevent transcriptional repression of the provirus.

The functional consequences of circular RNA (circRNA) expression on HIV-1 replication are largely unknown. Using a customized protocol involving direct RNA nanopore sequencing, here, we captured circRNAs from HIV-1-infected T cells and identified ciTRAN, a circRNA that modulates HIV-1 transcription. We found that HIV-1 infection induces ciTRAN expression in a Vpr-dependent manner and that ciTRAN interacts with SRSF1, a protein known to repress HIV-1 transcription. Our results suggest that HIV-1 hijacks ciTRAN to exclude serine/arginine-rich splicing factor 1 (SRSF1) from the viral transcriptional complex, thereby promoting efficient viral transcription. In addition, we demonstrate that an SRSF1-inspired mimic can inhibit viral transcription regardless of ciTRAN induction. The hijacking of a host circRNA thus represents a previously unknown facet of primate lentiviruses in overcoming transmission bottlenecks.

Improved loss-of-function CRISPR-Cas9 genome editing in human cells concomitant with inhibition of TGF-ß signaling.

Strategies to modulate cellular DNA repair pathways hold immense potential to enhance the efficiency of CRISPR-Cas9 genome editing platform. In the absence of a repair template, CRISPR-Cas9-induced DNA double-strand breaks are repaired by the endogenous cellular DNA repair pathways to generate loss-of-function edits. Here, we describe a reporter-based assay for expeditious measurement of loss-of-function editing by CRISPR-Cas9. An unbiased chemical screen performed using this assay enabled the identification of small molecules that promote loss-of-function editing. Iterative rounds of screens reveal Repsox, a TGF-ß signaling inhibitor, as a CRISPR-Cas9 editing efficiency enhancer. Repsox invariably increased CRISPR-Cas9 editing in a panel of commonly used cell lines in biomedical research and primary cells. Furthermore, Repsox-mediated editing enhancement in primary human CD4+ T cells enabled the generation of HIV-1-resistant cells with high efficiency. This study demonstrates the potential of transiently targeting cellular pathways by small molecules to improve genome editing for research applications and is expected to benefit gene therapy efforts.

Circular RNA as an Additional Player in the Conflicts Between the Host and the Virus.

Circular RNA (circRNA), a relatively new member of the non-coding RNA family, has spurred great interest among researchers following its discovery as a ubiquitous class within the RNA world. Rapid progress in circRNA biology has coincided with its identification in a plethora of diverse roles including regulation of gene expression and probable coding potential, as well as competing interactions with proteins and microRNAs in various pathological conditions. Emerging evidence suggests that circRNAs also function in viral infections. The deregulation of circRNAs during viral infection has prompted investigations into the possibilities of circRNA as a competing endogenous RNA (ceRNA) that modulates response to infection. Recently, viruses have been shown to encode circRNAs with proviral functions, providing a strong impetus for focused efforts to elucidate the networks coaxed by circRNAs during infection. This review elaborates on recent insights gained on the roles of circRNAs during virus infection and immunity.

Coelacanth SERINC2 Inhibits HIV-1 Infectivity and Is Counteracted by Envelope Glycoprotein from Foamy Virus.

SERINC5 restricts nef-defective HIV-1 by affecting early steps of the virus life cycle. Distantly related retroviruses with a wide host range encode virulent factors in response to challenge by SERINC5. However, the evolutionary origins of this antiretroviral activity, its prevalence among the paralogs, and its ability to target retroviruses remain understudied. In agreement with previous studies, we found that four human SERINC paralogs inhibit nef-defective HIV-1, with SERINC2 being an exception. Here, we demonstrate that this lack of activity in human SERINC2 is associated with its post-whole-genome duplication (post-WGD) divergence, as evidenced by the ability of pre-WGD orthologs from Saccharomyces cerevisiae and flies and a post-WGD-proximate SERINC2 from coelacanths to inhibit the virus. Intriguingly, Nef is unable to counter coelacanth SERINC2, indicating that such activity was directed toward other retroviruses found in coelacanths (like foamy viruses). However, foamy virus-derived vectors are intrinsically resistant to the action of SERINC2, and we show that the foamy virus envelope confers this resistance by affecting its steady-state levels. Our study highlights an ancient origin of antiretroviral activity in SERINCs and a hitherto-unknown interaction with a foamy virus. IMPORTANCESERINC5 constitutes a critical barrier to the propagation of retroviruses, as highlighted by parallel emergence of anti-SERINC5 activities among distant retroviral lineages. Therefore, understanding the origin and evolution of these host factors will provide key information about virus-host relationships that can be exploited for future drug development. Here, we show that SERINC5-mediated nef-defective HIV-1 infection inhibition is evolutionarily conserved. SERINC2 from coelacanth restricts HIV-1, and it was functionally adapted to target foamy viruses. Our findings provide insights into the evolutionary origin of antiretroviral activity in the SERINC gene family and uncover the role of SERINCs in shaping the long-term conflicts between retroviruses and their hosts.

From Entry to Egress: Strategic Exploitation of the Cellular Processes by HIV-1.

HIV-1 employs a rich arsenal of viral factors throughout its life cycle and co-opts intracellular trafficking pathways. This exquisitely coordinated process requires precise manipulation of the host microenvironment, most often within defined subcellular compartments. The virus capitalizes on the host by modulating cell-surface proteins and cleverly exploiting nuclear import pathways for post entry events, among other key processes. Successful virus-cell interactions are indeed crucial in determining the extent of infection. By evolving defenses against host restriction factors, while simultaneously exploiting host dependency factors, the life cycle of HIV-1 presents a fascinating montage of an ongoing host-virus arms race. Herein, we provide an overview of how HIV-1 exploits native functions of the host cell and discuss recent findings that fundamentally change our understanding of the post-entry replication events.

Multifunctional ionic porous frameworks for CO2 conversion and combating microbes.

Porous organic frameworks (POFs) with a heteroatom rich ionic backbone have emerged as advanced materials for catalysis, molecular separation, and antimicrobial applications. The loading of metal ions further enhances Lewis acidity, augmenting the activity associated with such frameworks. Metal-loaded ionic POFs, however, often suffer from physicochemical instability, thereby limiting their scope for diverse applications. Herein, we report the fabrication of triaminoguanidinium-based ionic POFs through Schiff base condensation in a cost-effective and scalable manner. The resultant N-rich ionic frameworks facilitate selective CO2 uptake and afford high metal (Zn(ii): 47.2%) loading capacity. Owing to the ionic guanidinium core and ZnO infused mesoporous frameworks, Zn/POFs showed pronounced catalytic activity in the cycloaddition of CO2 and epoxides into cyclic organic carbonates under solvent-free conditions with high catalyst recyclability. The synergistic effect of infused ZnO and cationic triaminoguanidinium frameworks in Zn/POFs led to robust antibacterial (Gram-positive, Staphylococcus aureus and Gram-negative, Escherichia coli) and antiviral activity targeting HIV-1 and VSV-G enveloped lentiviral particles. We thus present triaminoguanidinium-based POFs and Zn/POFs as a new class of multifunctional materials for environmental remediation and biomedical applications.

Catalytic Enantioselective 1,3-Alkyl Shift in Alkyl Aryl Ethers: Efficient Synthesis of Optically Active 3,3'-Diaryloxindoles.

Reported is the first organocatalytic asymmetric 1,3-alkyl shift in alkyl aryl ethers for the synthesis of chiral 3,3'-diaryloxindoles using a chiral Brønsted acid catalyst. Preliminary results showed that each enantiomer of the 3,3'-diaryloxindole, and a racemic mixture, showed different antiproliferative activities against HeLa cell lines by using an MTT assay.