Ferroptosis-related genes, a novel therapeutic target for focal segmental glomerulosclerosis.

Recent studies have suggested that ferroptosis participates in various renal diseases. However, its effect on focal segmental glomerulosclerosis remains unclear. This study analyzed the GSE125779 and GSE121211 datasets to identify the differentially expressed genes (DEGs) in renal tubular samples with and without FSGS. The Cytoscape was used to construct the protein-protein interaction network. Moreover, the ferroptosis-related genes (FRGs) were obtained from the ferroptosis database, while ferroptosis-related DEGs were obtained by intersection with DEGs. The target genes were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The GSE108112 dataset was used to verify the expression of target FRGs. Besides, we built the mRNA-miRNA network regarding FRGs using the NetworkAnalyst database, and circRNAs corresponding to key miRNAs were predicted in the ENCORI database. In this study, 16 ferroptosis-related DEGs were identified between FSGS and healthy subjects, while five co-expressed genes were obtained by three topological algorithms in Cytoscape. These included the most concerned Hub genes JUN, HIF1A, ALB, DUSP1 and ATF3. The KEGG enrichment analysis indicated that FRGs were associated with mitophagy, renal cell carcinoma, and metabolic pathways. Simultaneously, the co-expressed hub genes were analyzed to construct the mRNA-miRNA interaction network and important miRNAs such as hsa-mir-155-5p, hsa-mir-1-3p, and hsa-mir-124-3p were obtained. Finally, 75 drugs targeting 54 important circRNAs and FRGs were predicted. This study identified the Hub FRGs and transcriptomic molecules from FSGS in renal tubules, thus providing novel diagnostic and therapeutic targets for FSGS.

The Rpf107 gene, a homolog of LOR, is required for the symbiotic nodulation of Robinia pseudoacacia.

MAIN CONCLUSION: Rpf107 is involved in the infection process of rhizobia and the maintenance of symbiotic nitrogen fixation in black locust root nodules. The LURP-one related (LOR) protein family plays a pivotal role in mediating plant defense responses against both biotic and abiotic stresses. However, our understanding of its function in the symbiotic interaction between legumes and rhizobia remains limited. Here, Rpf107, a homolog of LOR, was identified in Robinia pseudoacacia (black locust). The subcellular localization of Rpf107 was analyzed, and its function was investigated using RNA interference (RNAi) and overexpression techniques. The subcellular localization assay revealed that Rpf107 was mainly distributed in the plasma membrane and nucleus. Rpf107 silencing prevented rhizobial infection and hampered plant growth. The number of infected cells in the nitrogen fixation zone of the Rpf107-RNAi nodules was also noticeably lower than that in the control nodules. Notably, Rpf107 silencing resulted in bacteroid degradation and the premature aging of nodules. In contrast, the overexpression of Rpf107 delayed the senescence of nodules and prolonged the nitrogen-fixing ability of nodules. These results demonstrate that Rpf107 was involved in the infection of rhizobia and the maintenance of symbiotic nitrogen fixation in black locust root nodules. The findings reveal that a member of the LOR protein family plays a role in leguminous root nodule symbiosis, which is helpful to clarify the functions of plant LOR protein family and fully understand the molecular mechanisms underlying legume-rhizobium symbiosis.

[Cloning and functional verification of PhAEP gene, a key enzyme for biosynthesis of heterophyllin A in Pseudostellaria heterophylla].

This paper aimed to study the role of asparagine endopeptidase(AEP) gene in the biosynthesis mechanism of cyclic peptide compounds in Pseudostellaria heterophylla. The transcriptome database of P. heterophylla was systematically mined and screened, and an AEP gene, tentatively named PhAEP, was successfully cloned. The heterologous function verification by Nicotiana benthamiana showed that the expression of the gene played a role in the biosynthesis of heterophyllin A in P. heterophylla. Bioinformatics analysis showed that the cDNA of PhAEP was 1 488 bp in length, encoding 495 amino acids with a molecular weight of 54.72 kDa. The phylogenetic tree showed that the amino acid sequence encoded by PhAEP was highly similar to that of Butelase-1 in Clitoria ternatea, reaching 80%. The sequence homology and cyclase active site analysis revealed that the PhAEP enzyme may specifically hydrolyse the C-terminal Asn/Asp(Asx) site of the core peptide in the HA linear precursor peptide of P. heterophylla, thereby participating in the ring formation of the linear precursor peptide. The results of real-time quantitative polymerase chain reaction(RT-qPCR) showed that the expression level of PhAEP was the highest in fruits, followed by in roots, and the lowest in leaves. The heterophyllin A of P. heterophylla was detected in N. benthamiana that co-expressed PrePhHA and PhAEP genes instantaneously. In this study, the PhAEP gene, a key enzyme in the biosynthesis of heterophyllin A in P. heterophylla, has been successfully cloned, which lays a foundation for further analysis of the molecular mechanism of PhAEP enzyme in the biosynthesis of heterophyllin A in P. heterophylla and has important significance for the study of synthetic biology of cyclic peptide compounds in P. heterophylla.

[The Involvement of the Gagr Gene, a Domesticated gag Retrovirus Gene, in the Stress-Response Pathway in Different Drosophila Species].

The Gagr gene is a domesticated gag retroelement gene in Drosophila melanogaster, whose function is associated with the stress response. The protein products of the Gagr gene and its homologues in different Drosophila species have a highly conserved structure; however, they demonstrate variability in the promoter region of the gene, which is apparently associated with the gradual acquisition of a new function and involvement in new signaling pathways. In this work, we studied the effect of oxidative stress induced by ammonium persulfate on the survival of various species of the genus Drosophila (D. melanogaster, D. mauritiana, D. simulans, D. yakuba, D. teissieri, and D. pseudoobscura), analyzed the correlation between the structure of promoter regions and stress-induced changes in the expression of the Gagr gene and its homologues in different Drosophila species, and compared the stress-induced changes in the expression of oxidative stress markers: the Jak-STAT signaling pathway activator gene upd3, Jak-STAT pathway effector vir-1, and IMD signaling pathway target Rel. It was found that in D. simulans and D. mauritiana sensitivity to ammonium persulfate is significantly increased, which correlates with a reduced level of transcription of vir-1 gene orthologues. The latter is due to a decrease in the number of binding sites for the transcription factor STAT92E, a component of the Jak-STAT signaling pathway, in the vir-1 promoter region. Consistent changes in the expression of the Gagr, upd3, and vir-1 genes are observed in all species of the melanogaster subgroup, except for D. pseudoobscura, which indicates an increase in the role of Gagr in the regulation of stress response pathways during the phylogenesis of the genus Drosophila.

Subtype classification based on t cell proliferation-related regulator genes and risk model for predicting outcomes of lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD), the major lung cancer histotype, represents 40% lung cancers. Currently, outcomes are remarkably different in LUAD patients with similar AJCC/UICC-TNM features. T cell proliferation-related regulator genes (TPRGs) relate to the proliferation, activity and function of T cells and tumor progression. The values of TPRGs in classifying LUAD patients and predicting outcomes remain unknown. Methods: Gene expression profile and corresponding clinical data were downloaded from TCGA and the GEO databases. We systematically analyzed the expression profile characteristics of 35 TPRGs in LUAD patients and investigated the differences in overall survival (OS), biology pathway, immunity and somatic mutation between different TPRGs-related subtypes. Subsequently, we constructed a TPRGs-related risk model in TCGA cohort to quantify risk scores using LASSO cox regression analysis and then validated this risk model in two GEO cohorts. LUAD patients were divided into high- and low-risk subtypes according to the median risk score. We systematically compared the biology pathway, immunity, somatic mutation and drug susceptibility between the two risk subtypes. Finally, we validate biological functions of two TPRGs-encoded proteins (DCLRE1B and HOMER1) in LUAD cells A549. Results: We identified different TPRGs-related subtypes (including cluster 1/cluster A and its counterpart cluster 2/cluster B). Compared to the cluster 1/cluster A subtype, cluster 2/cluster B subtype tended to have a prominent survival advantage with an immunosuppressive microenvironment and a higher somatic mutation frequency. Then, we constructed a TPRGs-related 6-gene risk model. The high-risk subtype characterized by higher somatic mutation frequency and lower immunotherapy response had a worse prognosis. This risk model was an independent prognostic factor and showed to be reliable and accurate for LUAD classification. Furthermore, subtypes with different risk scores were significantly associated with drug sensitivity. DCLRE1B and HOMER1 suppressed cell proliferation, migration and invasion in LUAD cells A549, which was in line with their prognostic values. Conclusion: We construed a novel stratification model of LUAD based on TPRGs, which can accurately and reliably predict the prognosis and might be used as a predictive tool for LUAD patients.

Ca2+- and Voltage-Activated K+ (BK) Channels in the Nervous System: One Gene, a Myriad of Physiological Functions.

BK channels are large conductance potassium channels characterized by four pore-forming α subunits, often co-assembled with auxiliary ß and γ subunits to regulate Ca2+ sensitivity, voltage dependence and gating properties. BK channels are abundantly expressed throughout the brain and in different compartments within a single neuron, including axons, synaptic terminals, dendritic arbors, and spines. Their activation produces a massive efflux of K+ ions that hyperpolarizes the cellular membrane. Together with their ability to detect changes in intracellular Ca2+ concentration, BK channels control neuronal excitability and synaptic communication through diverse mechanisms. Moreover, increasing evidence indicates that dysfunction of BK channel-mediated effects on neuronal excitability and synaptic function has been implicated in several neurological disorders, including epilepsy, fragile X syndrome, mental retardation, and autism, as well as in motor and cognitive behavior. Here, we discuss current evidence highlighting the physiological importance of this ubiquitous channel in regulating brain function and its role in the pathophysiology of different neurological disorders.

Characterization of immune microenvironment infiltration and m6A regulator-mediated RNA methylation modification patterns in osteoarthritis.

Background: Few studies have been reported the potential role of N6-methyladenosine (m6A) modification in osteoarthritis (OA). We investigated the patterns of m6A modification in the immune microenvironment of OA. Methods: We evaluated the m6A modification patterns based on 22 m6A regulators in 139 OA samples and systematically associated these modification patterns with immune cell infiltration characteristics. The function of m6A phenotype-related differentially expressed genes (DEGs) was investigated using gene enrichment analysis. An m6A score model was constructed using principal component analysis (PCA), and an OA prediction model was established based on the key m6A regulators. We used real-time PCR analysis to detect the changes of gene expression in the cell model of OA. Results: Healthy and OA samples showed significant differences in the expression of m6A regulators. Nine key m6A regulators, two m6A modification patterns, m6A-related genes and two gene clusters were identified. Some m6A regulators had a strong correlation with each other. Gene clusters and m6A clusters have high similarity, and cluster A corresponds to a high m6A score. Immunocytes infiltration differed significantly between the two clusters, with the m6A cluster B and gene cluster B having more types of infiltrating immunocytes than cluster A. The predictive model can also predict the progression of OA through m6A regulators expression. The results of real-time PCR analysis showed that the gene expression in the cell model of OA is similar to that of the m6A cluster B. Conclusions: Our study reveals for the first time the potential regulatory mechanism of m6A modification in the immune microenvironment of OA. This study also sheds new light on the pathogenesis of OA.

clbP Gene, a Potential New Member of the ß-Lactamase Family.

The colibactin island (pks) of Escherichia coli formed by 19 genes (55-Kb), encodes non-ribosomal peptide (NRP) and polyketide (PK) synthases, which allow the synthesis of colibactin, a suspected hybrid PK-NRP compound that causes damage to DNA in eukaryotic cells. The clbP, an unusual essential gene, is found in the operon structure with the clbS gene in the pks-encoded machinery. Interestingly, the clbP gene has been annotated as a ß-lactamase but no previous study has reported its ß-lactamase characteristics. In this study, we (i) investigated the ß-lactamase properties of the clbP gene in silico by analysing its phylogenetic relationship with bacterial ß-lactamase and peptidase enzymes, (ii) compared its three-dimensional (3D) protein structure with those of bacterial ß-lactamase proteins using the Phyr2 database and PyMOL software, and (iii) evaluated in vitro its putative enzymatic activities, including ß-lactamase, nuclease, and ribonuclease using protein expression and purification from an E. coli BL21 strain. In this study, we reveal a structural configuration of toxin/antitoxin systems in this island. Thus, similar to the toxin/antitoxin systems, the role of the clbP gene within the pks-island gene group appears as an antitoxin, insofar as it is responsible for the activation of the toxin, which is colibactin. In silico, our analyses revealed that ClbP belonged to the superfamily of ß-lactamase, class C. Furthermore, in vitro we were unable to demonstrate its ß-lactamase activity, likely due to the fact that the clbP gene requires co-expression with other genes, such as the genes present in the pks-island (19 genes). More research is needed to better understand its actions, particularly with regards to antibiotics, and to discover whether it has any additional functions due to the importance of this gene and its toxicity.

1-Kestose Supplementation Increases Levels of a 5α-Reductase Gene, a Key Isoallolithocholic Acid Biosynthetic Gene, in the Intestinal Microbiota.

1-Kestose (kestose) is the smallest fructooligosaccharide component and shows a particularly high prebiotic function. Both kestose and the bile acid metabolite isoallolithocholic acid (isoalloLCA) are known to be beneficial for human health, especially in terms of immune homeostasis in the gastrointestinal system; however, the effect of kestose on the levels of microbial isoalloLCA producers remains to be clarified. IsoalloLCA is known to be produced by several members of the phylum Bacteroidota that carry the 5α-reductase (5AR) gene, a key isoalloLCA biosynthetic gene. Thus, we designed a specific primer set to detect the 5AR gene based on the consensus sequences of the genes from several isoalloLCA producers. Using real-time quantitative PCR with this primer set and fecal DNA samples, we compared the 5AR gene level (5ar-level) in the intestinal microbiota of a kestose-supplemented group (n=20) and a placebo group (n=16) before and after intake for 12 wk. The 5ar-level was significantly increased in the kestose-supplemented group (p=0.015), but not in the placebo group (p=0.379), indicating that kestose supplementation increased the 5ar-level in human intestinal microbiota. Our findings suggest that targeting functional gene levels could potentially be used to predict and understand the beneficial prebiotic effects associated with changes in gut microbiota.

Increasing the Grain Yield and Grain Protein Content of Common Wheat (Triticum aestivum) by Introducing Missense Mutations in the Q Gene.

Grain yield (GY) and grain protein content (GPC) are important traits for wheat breeding and production; however, they are usually negatively correlated. The Q gene is the most important domestication gene in cultivated wheat because it influences many traits, including GY and GPC. Allelic variations in the Q gene may positively affect both GY and GPC. Accordingly, we characterized two new Q alleles (Qs1 and Qc1-N8) obtained through ethyl methanesulfonate-induced mutagenesis. Compared with the wild-type Q allele, Qs1 contains a missense mutation in the sequence encoding the first AP2 domain, whereas Qc1-N8 has two missense mutations: one in the sequence encoding the second AP2 domain and the other in the microRNA172-binding site. The Qs1 allele did not significantly affect GPC or other processing quality parameters, but it adversely affected GY by decreasing the thousand kernel weight and grain number per spike. In contrast, Qc1-N8 positively affected GPC and GY by increasing the thousand kernel weight and grain number per spike. Thus, we generated novel germplasm relevant for wheat breeding. A specific molecular marker was developed to facilitate the use of the Qc1-N8 allele in breeding. Furthermore, our findings provide useful new information for enhancing cereal crops via non-transgenic approaches.

Drosophila transcription factor NF-Y suppresses transcription of the lipase 4 gene, a key gene for lipid storage.

The CCAAT motif-binding factor NF-Y consists of three different subunits, NF-YA, NF-YB, and NF-YC. Although it is suggested that NF-Y activity is essential for normal tissue homeostasis, survival, and metabolic function, its precise role in lipid metabolism is not clarified yet. In Drosophila, eye disc specific knockdown of Drosophila NF-YA (dNF-YA) induced aberrant morphology of the compound eye, the rough eye phenotype in adults and mutation of the lipase 4 (lip4) gene suppressed the rough eye phenotype. RNA-seq analyses with dNF-YA knockdown third instar larvae identified the lip4 gene as one of the genes that are up-regulated by the dNF-YA knockdown. We identified three dNF-Y-binding consensuses in the 5'flanking region of the lip4 gene, and a chromatin immunoprecipitation assay with the specific anti-dNF-YA IgG demonstrated dNF-Y binding to this genomic region. The luciferase transient expression assay with cultured Drosophila S2 cells and the lip4 promoter-luciferase fusion genes with and without mutations in the dNF-Y-binding consensuses showed that each of the three dNF-Y consensus sequences negatively regulated lip4 gene promoter activity. Consistent with these results, qRT-PCR analysis with the dNF-YA knockdown third instar larvae revealed that endogenous lip4 mRNA levels were increased by the knockdown of dNF-YA in vivo. The specific knockdown of dNF-YA in the fat body with the collagen-GAL4 driver resulted in smaller oil droplets in the fat body cells. Collectively, these results suggest that dNF-Y is involved in lipid storage through its negative regulation of lip4 gene transcription.

Threonyl-tRNA synthetase gene, a potential target for RNAi-based control of three rice planthoppers.

BACKGROUND: RNA interference (RNAi) has potential as a new strategy for pest control. However, the current overemphasis on the control of a single pest increased control costs. The aim of this study was to find a green method of controlling several pests without affecting the natural enemies with a single target gene. One possible RNAi target is the threonyl-tRNA synthetase (ThrRS), which is conserved and plays a significant role in protein biosynthesis. RESULTS: In this study, one threonyl-tRNA synthetase gene (NlthrS) was identified from the brown planthopper (Nilaparvata lugens). Spatio-temporal expression pattern analysis showed that NlthrS was highly expressed in the ovary, late embryogenesis, nymphs and female adults. In addition, RNAi-mediated knockdown of NlthrS caused 85.6% nymph mortality, 100% female infertility, molting disorder, extended nymph duration and shortened adult longevity. Target-specific results were obtained when dsNlthrS was used to interfere with the whiteback planthopper (Sogatella furcifera), small brown planthopper (Laodelphax striatellus), zig-zag winged leafhopper (Inazuma dorsalis) and their natural enemy (green mirid bug, Cyrtorhinus lividipennis). In addition, dsNlthrS could cause high mortalities of three species of planthoppers (85.6-100%), while only dsNlthrS-1 led to the death (97.3%) of I. dorsalis that was not affected by dsNlthrS-2. Furthermore, neither dsNlthrS-1 nor dsNlthrS-2 could influence the survival of C. lividipennis. CONCLUSION: The results reveal the biological functions of ThrRS in N. lugens in addtion to its protein synthesis, deepening our understanding of tRNA synthase in insects and providing a new method for the control of several rice pests via one dsRNA design. © 2022 Society of Chemical Industry.

Deletion and Overexpression of the AnOTAbzip Gene, a Positive Regulator of Ochratoxin A Biosynthesis in Aspergillus niger.

The ochratoxin A (OTA) biosynthetic gene cluster includes a bZIP transcription factor (TF) gene (OTAbzip) that has been identified in different fungal species. However, most previous studies identified the OTAbzip gene in ochratoxigenic fungi using bioinformatics methods, while few studies focused on deleting the gene, let alone overexpressing it, to characterize the function of the OTAbZIP TF. Here, we characterized the AnOTAbZIP TF in an ochratoxigenic isolate of Aspergillus niger by deleting and overexpressing the AnOTAbzip gene and examining the role of AnOTAbZIP in morphological development, OTA biosynthesis, and pathogenicity. Chemical and gene expression analyses revealed that AnOTAbZIP positively regulates OTA biosynthesis, since the loss of OTA production and the downregulation of the OTA biosynthetic genes were observed in the ΔAnOTAbzip strain, compared with the wild-type (WT) and OE::AnOTAbzip strains. In terms of pathogenicity, the ΔAnOTAbzip strain produced a greater lesion on grape berries, especially with respect to the OE::AnOTAbzip strain, rather than WT. Finally, the ΔAnOTAbzip strain was also more tolerant to oxidative stress with respect to the OE::AnOTAbzip and WT strains in that order. These new findings improve our understanding of the AnOTAbZIP regulatory mechanism and help develop strategies to attenuate plant pathogenicity and reduce OTA biosynthesis of A. niger.

The Foraging Gene, a New Environmental Adaptation Player Involved in Xenobiotic Detoxification.

Foraging is vital for animals, especially for food. In Drosophila melanogaster, this behavior is controlled by the foraging gene (for) which encodes a cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG). In wild populations of Drosophila, rover individuals that exhibit long foraging trails and sitter individuals that exhibit short ones coexist and are characterized by high and low levels of PKG activity, respectively. We, therefore, postulated that rover flies are more exposed to environmental stresses, including xenobiotics contamination, than sitter flies. We then tested whether these flies differed in their ability to cope with xenobiotics by exposing them to insecticides from different chemical families. We performed toxicological tests and measured the activity and expression levels of different classes of detoxification enzymes. We have shown that a link exists between the for gene and certain cytochrome P450-dependent activities and that the expression of the insecticide-metabolizing cytochrome P450 Cyp6a2 is controlled by the for gene. An unsuspected regulatory pathway of P450s expression involving the for gene in Drosophila is revealed and we demonstrate its involvement in adaptation to chemicals in the environment. This work can serve as a basis for reconsidering adaptation to xenobiotics in light of the behavior of species, including humans.

NLM-Gene, a richly annotated gold standard dataset for gene entities that addresses ambiguity and multi-species gene recognition.

The automatic recognition of gene names and their corresponding database identifiers in biomedical text is an important first step for many downstream text-mining applications. While current methods for tagging gene entities have been developed for biomedical literature, their performance on species other than human is substantially lower due to the lack of annotation data. We therefore present the NLM-Gene corpus, a high-quality manually annotated corpus for genes developed at the US National Library of Medicine (NLM), covering ambiguous gene names, with an average of 29 gene mentions (10 unique identifiers) per document, and a broader representation of different species (including Homo sapiens, Mus musculus, Rattus norvegicus, Drosophila melanogaster, Arabidopsis thaliana, Danio rerio, etc.) when compared to previous gene annotation corpora. NLM-Gene consists of 550 PubMed abstracts from 156 biomedical journals, doubly annotated by six experienced NLM indexers, randomly paired for each document to control for bias. The annotators worked in three annotation rounds until they reached complete agreement. This gold-standard corpus can serve as a benchmark to develop & test new gene text mining algorithms. Using this new resource, we have developed a new gene finding algorithm based on deep learning which improved both on precision and recall from existing tools. The NLM-Gene annotated corpus is freely available at ftp://ftp.ncbi.nlm.nih.gov/pub/lu/NLMGene. We have also applied this tool to the entire PubMed/PMC with their results freely accessible through our web-based tool PubTator (www.ncbi.nlm.nih.gov/research/pubtator).

Evaluation of Q Gene Mycobacteria: A novel and easy nucleic acid chromatography method for mycobacterial species identification.

OBJECTIVES: A simple, rapid, and new diagnostic test for mycobacteria, named Q Gene Mycobacteria, has been developed. It is based on multiplex PCR using primers harbouring DNA tags combined with a dipstick nucleic acid chromatography method, which does not require the denaturation of PCR products for hybridization and can identify five species of mycobacteria including Mycobacterium tuberculosis complex (MTC), Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, and Mycobacterium gordonae. This study aimed to evaluate Q Gene Mycobacteria for the accurate identification of these five species. METHODS: A total of 340 mycobacterial strains/isolates were tested, of which 159 were type strains (four MTC and 155 non-tuberculosis mycobacteria (NTM) including four subspecies) and 181 were clinical isolates (18 M. tuberculosis, two Mycobacterium bovis Bacillus Calmette et Guérin (BCG), and 161 NTM comprising 16 species) collected from eight laboratories and hospitals in Japan. Species identification of NTM isolates was performed using the DNA-DNA hybridization method and/or direct sequencing of 16S rRNA, hsp65, and rpoB genes. Q Gene Mycobacteria was compared with above conventional methods for identifying the five species. RESULTS: Q Gene Mycobacteria showed excellent concordance for species identification, specifically 99.4% (158/159) for type strains and 99.4% (180/181) for clinical isolates. The two strains that were misidentified as M. gordonae were Mycobacterium paragordonae. As they are genetically close and there is few case reports of M. paragordonae, it might not be a serious critical issue to distinguish M. paragordonae from M. gordonae. CONCLUSIONS: Q Gene Mycobacteria was able to identify frequently isolated mycobacterial species accurately and easily. Therefore, Q Gene Mycobacteria could be a useful tool for the identification of specific mycobacteria in clinical laboratories.

Host Restriction Factors APOBEC3G/3F and Other Interferon-Related Gene Expressions Affect Early HIV-1 Infection in Northern Pig-Tailed Macaque (Macaca leonina).

The northern pig-tailed macaques (NPMs) lack TRIM5α, an antiviral restriction factor, and instead have TRIM5-CypA. In our previous study, we demonstrated that HIV-1NL4-3 successfully infected NPMs and formed a long-term viral reservoir in vivo. However, the HIV-1-infected NPMs showed relatively high viremia in the first 6 weeks of infection, which declined thereafter suggesting that HIV-1 NL4-3 infection in these animals was only partly permissive. To optimize HIV-1 infection in NPMs therefore, we generated HIV-1NL4-R3A and stHIV-1sv, and infected NPMs with these viruses. HIV-1NL4-R3A and stHIV-1sv can replicate persistently in NPMs during 41 weeks of acute infection stage. Compared to the HIV-1NL4-R3A, stHIV-1sv showed a notably higher level of replication, and the NPMs infected with the latter induced a more robust neutralizing antibody but a weaker cellular immune response. In addition, IFN-I signaling was significantly up-regulated with the viral replication, and was higher in the stHIV-1sv infected macaques. Consequently, the sequences of pro-viral env showed fewer G-A hyper-mutations in stHIV-1sv, suggesting that vif gene of SIV could antagonize the antiviral effects of APOBEC3 proteins in NPMs. Taken together, NPMs infected with HIV-1NL4-R3A and stHIV-1sv show distinct virological and immunological features. Furthermore, interferon-related gene expression might play a role in controlling primary HIV-1NL4-R3A and stHIV-1sv replication in NPMs. This result suggests NPM is a potential HIV/AIDS animal model.