Viruses that establish latent infections have evolved unique mechanisms to avoid host immune recognition. Maintenance proteins of these viruses regulate their synthesis to levels sufficient for maintaining persistent infection but below threshold levels for host immune detection. The mechanisms governing this finely tuned regulation of viral latency are unknown. Here we show that mRNAs encoding gammaherpesviral maintenance proteins contain within their open reading frames clusters of unusual structural elements, G-quadruplexes, which are responsible for the cisacting regulation of viral mRNA translation. By studying the Epstein-Barr virus-encoded nuclear antigen 1 (EBNA1) mRNA, we demonstrate that destabilization of G-quadruplexes using antisense oligonucleotides increases EBNA1 mRNA translation. In contrast, pretreatment with a G-quadruplex-stabilizing small molecule, pyridostatin, decreases EBNA1 synthesis, highlighting the importance of G-quadruplexes within virally encoded transcripts as unique regulatory signals
Antigen-specific CD8+ T cells can destroy epithelium expressing HPV16 E7 tumor antigen, but presentation of E7 antigen from skin is insufficient to reactivate memory CD8+ T cells induced by immunotherapy. Thus, effective cancer immunotherapy in humans may need to invoke sufficient effector as well as memory T cells.
Abstract. Expanding of karst rocky desertification (RD) area in southwestern China is strangling the sustainable development of local agricultural economy. It is important to evaluate the soil fertility at RD regions for the sustainable management of karst lands. The changes in 19 different soil fertilityrelated variables along a gradient of karst rocky desertification were investigated in five different counties belonging to the central Hunan province in China. We used principal component analysis method to calculate the soil data matrix and obtained a standardized integrate soil fertility (ISF) indicator to reflect RD grades. The results showed that the succession of RD had different impacts on soil fertility indicators. The changing trend of total organic carbon (TOC), total nitrogen (TN), available phosphorus, microbial biomass carbon (MBC), and microbial biomass nitrogen (MBN) was potential RD (PRD) > light RD (LRD) > moderate RD (MRD) > intensive RD (IRD), whereas the changing trend of other indicators was not entirely consistent with the succession of RD. The degradation trend of ISF was basically parallel to the aggravation of RD, and the strength of ISF mean values were in the order of PRD > LRD > MRD > IRD. The TOC, MBC, and MBN could be regarded as the key indicators to evaluate the soil fertility.
Abstract. Expanding of karst rocky desertification (RD) area in southwestern China has led to destructed ecosystem and local economic development lagging behind. It is important to understand the soil fertility at RD regions for the sustainable management of karst lands. The effects of the succession of RD on soil fertility were studied by investigating the stands and analyzing the soil samples with different RD grades in the central Hunan province, China, using the principal component analysis method. The results showed that the succession of RD had different impacts on soil fertility indicators. The changing trend of total organic carbon (TOC), total nitrogen (TN), available phosphorous (AP), microbial biomass carbon (MBC), and microbial biomass nitrogen (MBN) out of 19 selected indicators in different RD regions was: potential RD (PRD) > light RD (LRD) > moderate RD (MRD) > intensive RD (IRD), whereas the changing trend of other indicators was not entirely consistent with the succession of RD. The degradation trend of soil fertility was basically parallel to the aggravation of RD, and the strength of integrated soil fertility was in the order of PRD > MRD > LRD > IRD. The TOC, total phosphorus (TP), cation exchange capacity (CEC), MBC, MBN, microbial mass phosphorous (MBP), and bulk density (BD) could be regarded as the key indicators to evaluate the soil fertility due to their close correlations to the integrated fertility.
Unique purine-rich mRNA sequences embedded in the coding sequences of a distinct group of gammaherpesvirus maintenance proteins underlie the ability of the latently infected cell to minimize immune recognition. The Epstein-Barr virus nuclear antigen, EBNA1, a well characterized lymphocryptovirus maintenance protein has been shown to inhibit in cis antigen presentation, due in part to a large internal repeat domain encoding glycine and alanine residues (GAr) encoded by a purine-rich mRNA sequence. Recent studies have suggested that it is the purine-rich mRNA sequence of this repeat region rather than the encoded GAr polypeptide that directly inhibits EBNA1 self-synthesis and contributes to immune evasion. To test this hypothesis, we generated a series of EBNA1 internal repeat frameshift constructs and assessed their effects on cis-translation and endogenous antigen presentation. Diverse peptide sequences resulting from alternative repeat reading frames did not alleviate the translational inhibition characteristic of EBNA1 self-synthesis or the ensuing reduced surface presentation of EBNA1-specific peptide-MHC class I complexes. Human cells expressing the EBNA1 frameshift variants were also poorly recognized by antigen-specific T-cells. Furthermore, a comparative analysis of the mRNA sequences of the corresponding repeat regions of different viral maintenance homologues highlights the high degree of identity between the nucleotide sequences despite very little homology in the encoded amino acid sequences. Based on these combined observations, we propose that the cis-translational inhibitory effect of the EBNA1 internal repeat sequence operates mechanistically at the nucleotide level, potentially through RNA secondary structural elements, and is unlikely to be mediated through the GAr polypeptide. The demonstration that the EBNA1 repeat mRNA sequence and not the encoded protein sequence underlies immune evasion in this class of virus suggests a novel approach to therapeutic development through the use of anti-sense strategies or small molecules targeting EBNA1 mRNA structure.
Human cytomegalovirus (HCMV) disease is a major cause of morbidity and mortality in neonates and immunocompromised populations, such as transplant recipients and HIV-infected patients. The development of a vaccine to prevent HCMV infection or disease has been assigned the highest priority by the US Institute of Medicine. Although, after 30 years of intensive study, a clinically licensed vaccine is still not available, significant progress has been made in the field of HCMV vaccine development, along with greater understanding of HCMV immunology, molecular biology and pathology. In recent years, new vaccine strategies have been developed that have shown promising results in preclinical studies and are able to induce HCMV-specific immune responses in clinical studies, although efficacy data are not yet available. Here we review the history of HCMV vaccine development and the current strategies in the development of new HCMV vaccines. We propose that research should focus on the development of a vaccine to prevent or control HCMV-related disease rather than to prevent infection, and that discerning strategies should be used for targeting HCMV disease in different clinical settings.
Porcine reproductive and respiratory syndrome (PRRS) is a highly contagious disease and the most economically important disease of the swine industry worldwide. Highly pathogenic-PRRS virus (HP-PRRSV) is a variant of PRRSV, which caused high morbidity and mortality. Scavenger receptor CD163, which contains nine scavenger receptor cysteine-rich (SRCR) domains, is a key entry mediator for PRRSV. A previous study demonstrated that SRCR domain 5 (SRCR5), encoded by exon 7, was essential for PRRSV infection in vitro. Here, we substituted exon 7 of porcine CD163 with the corresponding exon of human CD163-like 1 (hCD163L1) using a CRISPR/Cas9 system combined with a donor vector. In CD163Mut/Mut pigs, modifying CD163 gene had no adverse effects on hemoglobin-haptoglobin (Hb-Hp) complex clearance or erythroblast growth. In vitro infection experiments showed that the CD163 mutant strongly inhibited HP-PRRSV replication by inhibiting virus uncoating and genome release. Compared to wild-type (WT) pigs in vivo, HP-PRRSV-infected CD163Mut/Mut pigs showed a substantially decreased viral load in blood and relief from PRRSV-induced fever. While all WT pigs were dead, there of four CD163Mut/Mut pigs survived and recovered at the termination of the experiment. Our data demonstrated that modifying CD163 remarkably inhibited PRRSV replication and protected pigs from HP-PRRSV infection, thus establishing a good foundation for breeding PRRSV-resistant pigs via gene editing technology.
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