Retroviral Research Articles

Appropriate Exogenous Expression Stoichiometry of GATA4 as an Important Factor for Cardiac Reprogramming of Human Dermal Fibroblasts.

Reprogramming of human dermal fibroblasts (HDFs) into induced cardiomyocyte-like cells (iCMs) represents a promising strategy for human cardiac regeneration. Different cocktails of cardiac transcription factors can convert HDFs into iCMs, although with low efficiency and immature phenotype. Here, GATA4, MEF2C, TBX5, MESP1, and MYOCD (GMTMeMy for short) were used to reprogram HDFs by retrovirus infection. We found that the exogenous expression stoichiometry of GATA4 (GATA4 stoichiometry) significantly affected reprogramming efficiency. When 1/8 dosage of GATA4 virus (GATA4 dosage) plus MTMeMy was used, the reprogramming efficiency was obviously improved compared with average pooled virus encoding each factor, which measured, by the expression level of cardiac genes, the percentage of cardiac troponin T and alpha-cardiac myosin heavy-chain immunopositive cells and the numbers of iCMs showing calcium oscillation or beating synchronously in co-culture with mouse CMs. In addition, we prepared conditioned maintenance medium (CMM) by CM differentiation of H9 human embryonic stem cell line. We found that compared with traditional maintenance medium (TMM), CMM made iCMs show well-organized sarcomere formation and characteristic calcium oscillation wave earlier. These findings demonstrated that appropriate GATA4 stoichiometry was essential for cardiac reprogramming and some components in CMM were important for maturation of iCMs.

Prevalence and diagnosis of retroviral infections in cats

Cat retroviruses, feline immunodeficiency virus and feline leukemia virus cause diseases that have a wide range of clinical manifestations and forms of infection. Aretrospective analysis of data from the last three years in the studied hospitals showed that the infection of cats with retroviruses is 32.6% for FeLV and 13.6% for FIV from the number of infectious diseases. Such high rates indicate that one third of cats coming to veterinary clinics with infectious diseases are infected with retroviruses. These are primarily animals at risk that have free range. Early detection of such animals by a veterinarian is important for effective treatment and prevention of infection. We have adapted the algorithm for the diagnosis of retroviral infections in cats to domestic conditions and developed practical recommendations for veterinarians on the effective choice of laboratory methods for the diagnosis of retroviral infections. It was found that in clinics, the initial study of whole blood samples from infectiously infected cats was performed using commercial serological test systems VetExpert FIVAb + FeLVAg. After the results of the first stage of the study, the protocol of the nested polymerase chain reaction (PCR) was tested. DNA isolation was performed using the IndiSpin Pathogen Kit. OneTaq® 2X Master PCR mix with Standard Buffer and specific oligonucleotides were used in the study. Proviral DNA was detected in 100% of blood samples for the respective pathogens FIV and FeLV. All animals that were pre-diagnosed with FIV and VLC infection at the first stage of diagnosis were diagnosed with proviral DNA and confirmed at the second stage of diagnosis. The use of the nested PCR method significantly increases the sensitivity and specificity of the study. The first stage of diagnosis allows a veterinarian to determine the infectious status of the animal on the basis of which to choose a treatment strategy and prevent transmission of the pathogen. The second stage of diagnosis allows you to clarify the previous diagnosis and establish the form of infection. The presence of a clear and understandable diagnostic algorithm is necessary for effective control of FIV and FeLV. Key words: polymerase chain reaction, feline viral leukemia, feline immunodeficiency virus, molecular diagnostics, retroviral infections, diagnostic algorithm.

Convergent evolution of antiviral machinery derived from endogenous retrovirus truncated envelope genes in multiple species

Host genetic resistance to viral infection controls the pathogenicity and epidemic dynamics of infectious diseases. Refrex-1 is a restriction factor against feline leukemia virus subgroup D (FeLV-D) and an endogenous retrovirus (ERV) in domestic cats (ERV-DC). Refrex-1 is encoded by a subset of ERV-DC loci with truncated envelope genes and secreted from cells as a soluble protein. Here, we identified the copper transporter CTR1 as the entry receptor for FeLV-D and genotype I ERV-DCs. We also identified CTR1 as a receptor for primate ERVs from crab-eating macaques and rhesus macaques, which were found in a search of intact envelope genes capable of forming infectious viruses. Refrex-1 counteracted infection by FeLV-D and ERV-DCs via competition for the entry receptor CTR1; the antiviral effects extended to primate ERVs with CTR1-dependent entry. Furthermore, truncated ERV envelope genes found in chimpanzee, bonobo, gorilla, crab-eating macaque, and rhesus macaque genomes could also block infection by feline and primate retroviruses. Genetic analyses showed that these ERV envelope genes were acquired in a species- or genus-specific manner during host evolution. These results indicated that soluble envelope proteins could suppress retroviral infection across species boundaries, suggesting that they function to control retroviral spread. Our findings revealed that several mammalian species acquired antiviral machinery from various ancient retroviruses, leading to convergent evolution for host defense.

Predictors of time to recovery from postpartum hemorrhage in Debre Markos comprehensive specialized hospital, Northwest, Ethiopia, 2020/21

BackgroundPostpartum hemorrhage is one of the leading causes of maternal deaths worldwide. Early recovery is a performance indicator and better health outcome of patients with postpartum hemorrhage. Therefore, this study aimed to assess time to recovery from postpartum hemorrhage and its predictors in Debre Markos Comprehensive Specialized Hospital, Ethiopia, 2020.MethodsA retrospective follow-up study was conducted among 302 women who were diagnosed with postpartum hemorrhage from January 1, 2016 to December 31, 2020 at Debre Markos Comprehensive Specialized Hospital. Consecutive sampling technique was employed. To show the statistical significant difference between each group of variables, log rank test was used. Kaplan Meier analysis to estimate time to recovery and cox proportional-hazard regression analysis to determine independent predictors were carried out cautiously. Adjusted hazard ratio used to determine the strength of association.ResultThe median recovery time from postpartum hemorrhage was 13 h with range of (10 to 17 h). Blood transfusion (AHR: 1.8, 95% CI (1.39, 2.57)), NASG utilization (AHR: 6.5, 95% CI (4.58, 9.42)) fluid resuscitation (AHR 2.9, 95% CI (1.48, 5.54)), active management of third stage of labor (AHR: 1.7, 95% CI (1.18, 2.45)) and history of antenatal care follow-up (AHR: 2.6, 95% CI (1.91, 3.56)) were the predictors, which shorten the recovery time. Comorbidities like anemia at the time of admission (AHR: 0.62 95% CI (0.44, 0.89)), retroviral infection (AHR: 0.33, 95% CI (0.16, 0.67)) and Hepatitis B-Virus infection (AHR: 0.52, 95% CI (0.32, 0.82)) delay the recovery rate from postpartum hemorrhage.ConclusionMothers in North-West Ethiopia stays morbid from postpartum hemorrhage for more than half a day. Their recovery time was affected by Non-Pneumatic Anti-Shock Garment utilization, implementation of emergency management components like blood transfusion and fluid resuscitation, history of antenatal care follow up, and being comorbid with viral infections. Non-pneumatic anti-shock garment application to every mother with postpartum hemorrhage and implementation of proper emergency management approach are vital for rapid recovery from postpartum hemorrhage.

Activation of lnc-ALVE1-AS1 inhibited ALV-J replication through triggering the TLR3 pathway in chicken macrophage like cell line.

Endogenous retroviruses (ERVs) are remnants of the historical retroviral infections, and their derived transcripts with viral signatures are important sources of long noncoding RNAs (lncRNAs). We have previously shown that the chicken ERV-derived lncRNA lnc-ALVE1-AS1 exerts antiviral innate immunity in chicken embryo fibroblasts. However, it is not clear whether this endogenous retroviral RNA has a similar function in immune cells. Here, we found that lnc-ALVE1-AS1 was persistently inhibited in chicken macrophages after avian leukosis virus subgroup J (ALV-J) infection. Furthermore, overexpression of lnc-ALVE1-AS1 significantly inhibited the replication of exogenous ALV-J, whereas knockdown of lnc-ALVE1-AS1 promoted the replication of ALV-J in chicken macrophages. This phenomenon is attributed to the induction of antiviral innate immunity by lnc-ALVE1-AS1 in macrophages, whereas knockdown of lnc-ALVE1-AS1 had the opposite effect. Mechanistically, lnc-ALVE1-AS1 can be sensed by the cytosolic pattern recognition receptor TLR3 and trigger the type I interferons response. The present study provides novel insights into the antiviral defense of ERV-derived lncRNAs in macrophages and offers new strategies for future antiviral solutions.

Editorial: Host Immune Responses to Retroviral Infections

Editorial: Host Immune Responses to Retroviral Infections

Zhx2 Is a Candidate Gene Underlying Oxymorphone Metabolite Brain Concentration Associated with State-Dependent Oxycodone Reward.

Understanding the pharmacogenomics of opioid metabolism and behavior is vital to therapeutic success, as mutations can dramatically alter therapeutic efficacy and addiction liability. We found robust, sex-dependent BALB/c substrain differences in oxycodone behaviors and whole brain concentration of oxycodone metabolites. BALB/cJ females showed robust state-dependent oxycodone reward learning as measured via conditioned place preference when compared with the closely related BALB/cByJ substrain. Accordingly, BALB/cJ females also showed a robust increase in brain concentration of the inactive metabolite noroxycodone and the active metabolite oxymorphone compared with BALB/cByJ mice. Oxymorphone is a highly potent, full agonist at the mu opioid receptor that could enhance drug-induced interoception and state-dependent oxycodone reward learning. Quantitative trait locus (QTL) mapping in a BALB/c F2 reduced complexity cross revealed one major QTL on chromosome 15 underlying brain oxymorphone concentration that explained 32% of the female variance. BALB/cJ and BALB/cByJ differ by fewer than 10,000 variants, which can greatly facilitate candidate gene/variant identification. Hippocampal and striatal cis-expression QTL (eQTL) and exon-level eQTL analysis identified Zhx2, a candidate gene coding for a transcriptional repressor with a private BALB/cJ retroviral insertion that reduces Zhx2 expression and sex-dependent dysregulation of cytochrome P450 enzymes. Whole brain proteomics corroborated the Zhx2 eQTL and identified upregulated CYP2D11 that could increase brain oxymorphone in BALB/cJ females. To summarize, Zhx2 is a highly promising candidate gene underlying brain oxycodone metabolite levels. Future studies will validate Zhx2 and its site of action using reciprocal gene editing and tissue-specific viral manipulations in BALB/c substrains. SIGNIFICANCE STATEMENT: Our findings show that genetic variation can result in sex-specific alterations in whole brain concentration of a bioactive opioid metabolite after oxycodone administration, reinforcing the need for sex as a biological factor in pharmacogenomic studies. The cooccurrence of female-specific increased oxymorphone and state-dependent reward learning suggests that this minor yet potent and efficacious metabolite of oxycodone could increase opioid interoception and drug-cue associative learning of opioid reward, which has implications for cue-induced relapse of drug-seeking behavior and for precision pharmacogenetics.

Effects of prolonged exposure to ELF-EMF on HERVs expression in human melanoma cells.

The Human endogenous retroviruses (HERVs) are ancient remnants of exogenous retroviral infections. Their abnormal activation is associated with several diseases, such as cancer and autoimmunity. Epigenetic and environmental factors are probably playing essential roles in the expression of these elements. This study aimed to examine the 96-hour effects of ELF-EMF on HERV-H, K, and W expression in human melanoma cells. SK-MEL-37 cells (the human skin malignant melanoma) were continuously exposed to ELF-EMF (50 Hz) at 1.5 and 3 mT intensity for 96 hours. Following mRNA extraction, the expression level of HERV-H, K, and W was assessed by qPCR. According to our results, exposure to ELF-EMF intensities for 96 hours could significantly downregulate HERV-H, K, and W env gene expression (P<0.001). Our obtained data suggest that low intensity and long-term exposure to ELF-EMF may pave using this type of radiation as a novel therapeutic approach by neutralizing the HERVs upregulated expression in melanoma cells.

Lack of association between feline AB blood groups and retroviral status: a multicenter, multicountry study.

The relationship between blood group antigens and disease has been studied in humans. Blood types have been associated with both decreased and increased rates of various infections. In addition, blood group expression has been shown to vary with some cancers and gastrointestinal diseases. The objective of this study was to explore whether there is a relationship between blood type and retroviral infections in cats. Case records from a veterinary research laboratory, veterinary teaching hospitals and veterinary blood banks were retrospectively searched for cats where both blood type and retroviral status (feline leukemia [FeLV], feline immunodeficiency virus [FIV] or both) were listed (part 1). In addition, a sample of 33 cats with confirmed FIV infection was genotyped to determine blood groups (part 2). In part 1, 709 cats were identified, 119 of which were positive for retroviral infection. Among all cases, 621 were type A (87.6%), 68 were type B (9.6%) and 20 were type AB (2.8%). There was no relationship between overall retroviral status (positive/negative) and blood type (P = 0.43), between FeLV status and blood type (P = 0.86) or between FIV status and blood type (P = 0.94). There was no difference in the distribution of blood types between cats that were healthy and typed as possible blood donors vs sick cats that were typed prior to a possible transfusion (P = 0.13). In part 2, of the 33 FIV-infected cats, all blood group genotypes were identified, although this test did not discriminate type A from type AB. No relationship was identified between feline retroviral status and blood type in this study. The relationship between blood type and other disease states requires further study in veterinary patients.

Investigating Scarless Tissue Regeneration in Embryonic Wounded Chick Corneas.

Chick embryonic corneal wounds display a remarkable capacity to fully and rapidly regenerate, whereas adult wounded corneas experience a loss of transparency due to fibrotic scarring. The tissue integrity of injured embryonic corneas is intrinsically restored with no detectable scar formation. Given its accessibility and ease of manipulation, the chick embryo is an ideal model for studying scarless corneal wound repair. This protocol demonstrates the different steps involved in wounding the cornea of an embryonic chick in ovo. First, eggs are windowed at early embryonic ages to access the eye. Second, a series of in ovo physical manipulations to the extraembryonic membranes are conducted to ensure access to the eye is maintained through later stages of development, corresponding to when the three cellular layers of the cornea are formed. Third, linear cornea wounds that penetrate the outer epithelial layer and the anterior stroma are made using a microsurgical knife. The regeneration process or fully restored corneas can be analyzed for regenerative potential using various cellular and molecular techniques following the wounding procedure. Studies to date using this model have revealed that wounded embryonic corneas display activation of keratocyte differentiation, undergo coordinated remodeling of ECM proteins to their native three-dimensional macrostructure, and become adequately re-innervated by corneal sensory nerves. In the future, the potential impact of endogenous or exogenous factors on the regenerative process could be analyzed in healing corneas by using developmental biology techniques, such as tissue grafting, electroporation, retroviral infection, or bead implantation. The current strategy identifies the embryonic chick as a crucial experimental paradigm for elucidating the molecular and cellular factors coordinating scarless corneal wound healing.

A reduced complexity cross between BALB/c substrains identifies Zhx2 as a candidate gene underlying oxycodone metabolite brain concentration and state‐dependent learning of opioid reward

Understanding the pharmacokinetic profile of an opioid drug is vital to therapeutic success, and mutations in human PK genes can drastically alter therapeutic efficacy of opioids. We observed that at 30 min post‐oxycodone administration (1.25 mg/kg, i.p.) BALB/cJ mice showed a higher whole brain concentration of oxycodone, and female specific increase in noroxycodone, and oxymorphone compared to BALB/cByJ. This observation could explain the sex‐specific increase in oxycodone state‐dependent conditioned place preference in BALB/cJ female mice. To potentially link behavioral differences with PK differences, we conducted quantitative trait locus (QTL) mapping of whole brain oxycodone and metabolite concentrations in a reduced complexity cross (RCC). Because BALB/cJ and BALB/cByJ substrains differ by ~8,500 SNPs/indels, large genetic loci identified in an F2 cross are offset by a dramatic reduction in potentially causal variants. QTL mapping in 133 BALB/cJ x BALB/cByJ F2 mice (68F, 65M) revealed a single QTL on chromosome 15 associated with brain oxymorphone concentration that explained 29% of the phenotypic variance in females. Oxymorphone is a full agonist at the mu opioid receptor, with 8x the potency of oxycodone, and likely contributes to oxycodone addictive properties. Hippocampal and striatal cis‐eQTL analysis revealed genetically regulated expression of Zhx2, a transcriptional inhibitor known to harbor a private BALB/cJ retroviral insertion that dramatically reduces protein expression and leads to sex specific dysregulation of CYP450 genes within the liver. Whole brain mass spectroscopy proteomics in the parental strains corroborated these eQTL findings. We hypothesize that decreased Zhx2 expression leads to increased CYP450 expression, increased brain oxymorphone, and increased oxycodone‐induced behaviors. Interestingly, human GWAS of nicotine consumption identified a nominal association (10^‐7) with ZHX2, indicating that this transcriptional repressor could influence metabolism of multiple drugs of abuse.

Investigation of the prevalence of enzootic bovine leukosis in cattle in Ardahan region

Enzootic bovine leucosis (EBL) is a retroviral infection which is common all over the world. EBL causes huge economic losses due to milk loss, yield loss and death. In this study, it was aimed to investigate the presence of EBL by ELISA method from blood samples taken from cattle which were determined to be healthy because of clinical examination in Ardahan province and its counties in March-April 2021. For this, 500 cattle of different breeds and sexes between 1-10 years of age in different enterprises were sampled and the antibody response against EBL in the blood serum samples obtained was investigated with a commercial ELISA test kit. All 500 blood serum samples tested by ELISA were negative for EBL. As a result, EBL seropositivity was determined as 0% in Ardahan region as the studied area and time period.

Pathogenetic aspects of retroviral infections

Bovine leukemia and equine infectious anemia are registered in most regions of Ukraine and in many countries worldwide. This is accompanied by economic losses and reduced quality of livestock products, which determines the relevance of the study of retroviral infections, their diagnosis, and pathogenesis. The goal of our research was to find and improve the methodological foundations of the development of the pathological process for a more in-depth study of the etiology, pathogenesis, treatment, and prevention of retroviral infections. The object of the study was blood, lymph nodes, spleen, heart, lungs, liver, and kidneys for bovine leukemia and equine infectious anemia. Hematological, anatomical, histological, histochemical, morphometric, and statistical research methods were used for their study. The research group included 304 cattle aged 4–9 years and 42 horses, of which 25 were infected with the virus, and 17 were in the control group. It has been established that bovine leukemia and infectious anemia of horses is an irreversible pathological process characterized by slow progression, the presence of a latent or persistent form, with damage to cells, organs, and systems of the body, which leads to death. Infectious anemia of horses differs from leukemia of cattle by the hidden course of the pathological process. The pathogenesis of leukemia occurs in six stages, which we have identified and conventionally named.

Differential expression of an endogenous retroviral element [HERV-K(HML-6)] is associated with reduced survival in glioblastoma patients

Comprising approximately 8% of our genome, Human Endogenous RetroViruses (HERVs) represent a class of germline retroviral infections that are regulated through epigenetic modifications. In cancer cells, which often have epigenetic dysregulation, HERVs have been implicated as potential oncogenic drivers. However, their role in gliomas is not known. Given the link between HERV expression in cancer cell lines and the distinct epigenetic dysregulation in gliomas, we utilized a tailored bioinformatic pipeline to characterize and validate the glioma retrotranscriptome and correlate HERV expression with locus-specific epigenetic modifications. We identified robust overexpression of multiple HERVs in our cell lines, including a retroviral transcript, HML-6, at 19q13.43b in glioblastoma cells. HERV expression inversely correlated with loci-specific DNA methylation. HML-6 contains an intact open reading frame encoding a small envelope protein, ERVK3-1. Increased expression of ERVK3-1 in GBM patients is associated with a poor prognosis independent of IDH-mutational status. Our results suggest that not only is HML-6 uniquely overexpressed in highly invasive cell lines and tissue samples, but also its gene product, ERVK3-1, may be associated with reduced survival in GBM patients. These results may have implications for both the tumor biology of GBM and the role of ERVK3-1 as a potential therapeutic target.

A zebrafish reporter line reveals immune and neuronal expression of endogenous retrovirus.

ABSTRACTEndogenous retroviruses (ERVs) are fossils left in our genome from retrovirus infections of the past. Their sequences are part of every vertebrate genome and their random integrations are thought to have contributed to evolution. Although ERVs are mainly silenced by the host genome, they have been found to be activated in multiple disease states, such as auto-inflammatory disorders and neurological diseases. However, the numerous copies in mammalian genomes and the lack of tools to study them make defining their role in health and diseases challenging. In this study, we identified eight copies of the zebrafish endogenous retrovirus zferv. We created and characterised the first in vivo ERV reporter line in any species. Using a combination of live imaging, flow cytometry and single-cell RNA sequencing, we mapped zferv expression to early T cells and neurons. Thus, this new tool identified tissues expressing ERV in zebrafish, highlighting a potential role of ERV during brain development and strengthening the hypothesis that ERV play a role in immunity and neurological diseases. This transgenic line is therefore a suitable tool to study the function of ERV in health and diseases.

Detecting regressive feline leukemia infections and feline immunodeficiency coinfections in cats with clinical signs and hematological alterations related to retroviral infection

The infections caused by feline leukemia (FeLV) and feline immunodeficiency (fiv) viruses, are relevant in Feline Medicine due to the severe complications of the disease and related pathologies in domestic cats. This study describes clinical findings related to FeLV and fiv, regressive FeLV infections and identification of prevalent FeLV genotypes in domestic cats from Mérida, Yucatán, México. Hundred domestic cats with clinical manifestations of diseases associated with feline retrovirus infection in veterinary centers in Mérida, were submitted to a general physical examination, venipuncture to collect blood, and a quantitative hemogram. Detection of antigen (FeLV) and antibody (fiv) was used to estimate infection frequency. The percentage of regressive FeLV infections was determined by pcr of an env gene segment. Some FeLV amplified products were sequenced with the Sanger method and used to construct a phylogenetic tree. The predominant FeLV and fiv clinical infection findings were gingivitis, gingivostomatitis, periodontal disease and anemia. We found a 10% infection frequency for FeLV by antigen detection, and 17% for fiv by antibodies detection. pcr frequency detection for FeLV was 58%, and 52% were regressive infections. The phylogenetic analysis identified sequences associated with FeLV-A, and endogenous or recombinant FeLV that had not previously been identified in México. The frequency of infection by both retroviruses was higher in Mérida, Yucatán, than those described in previous studies. Cats with FeLV predominantly had regressive infections, but the role that endogenous or recombinant retroviruses play in disease development remains unknown.

The Role of the Inhibitory Ligand HVEM and Its Receptors CD160 and BTLA in the Regulation of Anti-retroviral T Cell Responses

Specific CD8+ T cells are crucial for the control of viruses. However, during many chronic viral infections these cells become dysfunctional. Immune checkpoint receptors, like PD-1 expressed on CD8+ T cells, contribute to this functional suppression during chronic infection. However, during the acute phase of infection virus-specific CD8+ T cells express high levels of PD-1 but are fully competent in killing virus-infected cells and there is increasing evidence that the biological activity of inhibitory receptors is strongly influenced by the availability of their respective ligands. We determined the expression of ligands for inhibitory receptors on infected myeloid cells during the acute phase of Friend retroviral (FV) infection. FV infection of granulocytes, monocytes, and macrophages strongly increased the cell surface expression of PD-L1 and the recently described ligand HVEM for inhibitory receptors BTLA and CD160. In addition, the infection of human myeloid cells in vitro with HIV also enhanced the expression of PD-L1 and HVEM. In infected mice, the upregulation of inhibitory ligands on infected cells was accompanied by enhanced frequencies of FV-specific CD8+ T cells that express PD-1, and the inhibitory receptors CD160 and BTLA. To define the functional effects of HVEM on activated CD8+ T cells, FV-infected mice were treated with blocking antibodies that prevented the interaction of HVEM with its two receptors, CD160 or BTLA, alone or in combination with anti-PD-L1 antibodies. Blocking the interaction of HVEM with CD160 and BTLA improved the production of cytotoxic molecules and the elimination of FV-infected cells. This effect was augmented when the therapy was combined with anti-PD-L1 antibodies, resulting in an additional expansion of cytotoxic CD8+ T cells. Thus, the ligand HVEM for the inhibitory receptors CD160 and BTLA downregulates the functionality of CD8+ T cells during retroviral infection and are potential targets for the immunomodulatory therapy of chronic viral infections.

Interaction of p10/p27 with macrophage migration inhibitory factor promotes avian leukosis virus subgroup J infection

Avian leukosis virus subgroup J (ALV-J), an oncogenic retrovirus, induces myelocytoma and various other tumors in broilers and layers. Many recent studies have shown that ALV-J can hijack host molecules to facilitate infection. However, the molecular mechanisms of this process are not clear. Here, we aimed to elucidate the molecular mechanisms contributing to ALV-J infection. ALV-J hijacked MIF via p10 and p27 to facilitate ALV-J infection. ALV-J persistently activated MIF expression in DF-1 cells, and MIF significantly facilitated ALV-J internalization and replication, which demonstrated by MIF overexpression and knockdown experiments and treatment with the MIF antagonist ISO-1. Furthermore, we found that the two subunit proteins of Gag, p10 and p27, interacted with MIF in the cytoplasm, respectively. These results suggested that the p10 and p27 subunit in Gag protein recruited MIF to promote ALV-J infection, providing insights into the roles of the p10/p27 and the host factor MIF in ALV-J infection. The finding may facilitate the development of new strategies for controlling ALV-J or retrovirus infections.

Beatrice Mintz (1921-2022): an innovator in embryo research and cancer biology

Beatrice Mintz (1921-2022): an innovator in embryo research and cancer biology

Retroviral infection of human neurospheres and use of stem Cell EVs to repair cellular damage

HIV-1 remains an incurable infection that is associated with substantial economic and epidemiologic impacts. HIV-associated neurocognitive disorders (HAND) are commonly linked with HIV-1 infection; despite the development of combination antiretroviral therapy (cART), HAND is still reported to affect at least 50% of HIV-1 infected individuals. It is believed that the over-amplification of inflammatory pathways, along with release of toxic viral proteins from infected cells, are primarily responsible for the neurological damage that is observed in HAND; however, the underlying mechanisms are not well-defined. Therefore, there is an unmet need to develop more physiologically relevant and reliable platforms for studying these pathologies. In recent years, neurospheres derived from induced pluripotent stem cells (iPSCs) have been utilized to model the effects of different neurotropic viruses. Here, we report the generation of neurospheres from iPSC-derived neural progenitor cells (NPCs) and we show that these cultures are permissive to retroviral (e.g. HIV-1, HTLV-1) replication. In addition, we also examine the potential effects of stem cell derived extracellular vesicles (EVs) on HIV-1 damaged cells as there is abundant literature supporting the reparative and regenerative properties of stem cell EVs in the context of various CNS pathologies. Consistent with the literature, our data suggests that stem cell EVs may modulate neuroprotective and anti-inflammatory properties in damaged cells. Collectively, this study demonstrates the feasibility of NPC-derived neurospheres for modeling HIV-1 infection and, subsequently, highlights the potential of stem cell EVs for rescuing cellular damage induced by HIV-1 infection.