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Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). ATL cells possess a CD4+ CD25+ phenotype, similar to that of regulatory T cells (Tregs). Tax has been reported to play a crucial role in the leukemogenesis of HTLV-1. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the viral genomic RNA, is expressed in all ATL cases and induces neoplastic and inflammatory disease in vivo. To test whether HBZ and Tax are both required for T cell malignancy, we generated HBZ/Tax double transgenic mice in which HBZ and Tax are expressed exclusively in CD4+ T cells. Survival was much reduced in HBZ/Tax double-transgenic mice compared with wild type littermates. Transgenic expression of HBZ and Tax induced skin lesions and T-cell lymphoma in mice, resembling diseases observed in HTLV-1 infected individuals. However, Tax single transgenic mice did not develop major health problems. In addition, memory CD4+ T cells and Foxp3+ Treg cells counts were increased in HBZ/Tax double transgenic mice, and their proliferation was enhanced. There was very little difference between HBZ single and HBZ/Tax double transgenic mice. Taken together, these results show that HBZ, in addition to Tax, plays a critical role in T-cell lymphoma arising from HTLV-1 infection. [ABSTRACT FROM AUTHOR]

Human T-cell leukemia virus type 1 (HTLV-1) causes both a neoplastic disease and inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 basic leucine zipper factor (HBZ) gene is encoded in the minus strand of the proviral DNA and is constitutively expressed in infected cells and ATL cells. HBZ increases the number of regulatory T (Treg) cells by inducing the Foxp3 gene transcription. Recent studies have revealed that some CD4+Foxp3+ T cells are not terminally differentiated but have a plasticity to convert to other T-cell subsets. Induced Treg (iTreg) cells tend to lose Foxp3 expression, and may acquire an effector phenotype accompanied by the production of inflammatory cytokines, such as interferon-γ (IFN-γ). In this study, we analyzed a pathogenic mechanism of chronic inflammation related with HTLV-1 infection via focusing on HBZ and Foxp3. Infiltration of lymphocytes was observed in the skin, lung and intestine of HBZ-Tg mice. As mechanisms, adhesion and migration of HBZ-expressing CD4+ T cells were enhanced in these mice. Foxp3−CD4+ T cells produced higher amounts of IFN-γ compared to those from non-Tg mice. Expression of Helios was reduced in Treg cells from HBZ-Tg mice and HAM/TSP patients, indicating that iTreg cells are predominant. Consistent with this finding, the conserved non-coding sequence 2 region of the Foxp3 gene was hypermethylated in Treg cells of HBZ-Tg mice, which is a characteristic of iTreg cells. Furthermore, Treg cells in the spleen of HBZ-transgenic mice tended to lose Foxp3 expression and produced an excessive amount of IFN-γ, while Foxp3 expression was stable in natural Treg cells of the thymus. HBZ enhances the generation of iTreg cells, which likely convert to Foxp3−T cells producing IFN-γ. The HBZ-mediated proinflammatory phenotype of CD4+ T cells is implicated in the pathogenesis of HTLV-1-associated inflammation. [ABSTRACT FROM AUTHOR]

Adult T-cell leukemia (ATL) patients and human T-cell leukemia virus-1 (HTLV-1) infected individuals succumb to opportunistic infections. Cell mediated immunity is impaired, yet the mechanism of this impairment has remained elusive. The HTLV-1 basic leucine zipper factor (HBZ) gene is encoded in the minus strand of the viral DNA and is constitutively expressed in infected cells and ATL cells. To test the hypothesis that HBZ contributes to HTLV-1 associated immunodeficiency, we challenged transgenic mice that express the HBZ gene in CD4 T cells (HBZ-Tg mice) with herpes simplex virus type 2 or Listeria monocytogenes, and evaluated cellular immunity to these pathogens. HBZ-Tg mice were more vulnerable to both infections than non-Tg mice. The acquired immune response phase was specifically suppressed, indicating that cellular immunity was impaired in HBZ-Tg mice. In particular, production of interferon-γ (IFN-γ) by CD4 T cells was suppressed in HBZ-Tg mice. HBZ suppressed transcription from the IFN-γ gene promoter in a CD4 T-cell intrinsic manner by inhibiting nuclear factor of activated T cells and the activator protein 1 signaling pathway. This study shows that HBZ inhibits CD4 T-cell responses by directly interfering with the host cell-signaling pathway, resulting in impaired cell-mediated immunity in vivo. [ABSTRACT FROM AUTHOR]

Adult T-cell leukemia (ATL) is a leukemia derived from mature CD4+ T cells and induced by human T-cell leukemia virus type 1 (HTLV-1) infection. Previous studies have revealed many possible molecular and cellular mechanisms of HTLV-1-induced leukemogenesis, but it still remains unknown how HTLV-1 transforms peripheral CD4 T cells in infected individuals. Given the fact that only 2-5% of infected individuals develop ATL, HTLV-1 infection alone is not sufficient for the transformation of infected cells. Host genetic and epigenetic abnormalities and host immunological status should be considered in attempting to understand the mechanism of the oncogenesis of ATL. Nonetheless, it is obvious that HTLV-1 infection dramatically increases the risk of leukemia generation from peripheral CD4 T-cells, in which the incidence of leukemia is quite low. Furthermore, the evidence that all ATL cases retain the HTLV-1 provirus, especially the 3' region, indicates that HTLV-1-encoded genes play a critical role in leukemogenesis. Since increasing evidence indicates that the HTLV-1 bZIP factor (HBZ) gene plays a significant role in the pathogenesis of HTLV-1, we will discuss the cellular and molecular mechanism of ATL generation from the virological point of view, particularly focusing on HBZ. [ABSTRACT FROM AUTHOR]

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic retrovirus that is etiologically associated with adult T-cell leukemia. The HTLV-1 bZIP factor (HBZ), which is encoded by the minus strand of the provirus, is involved in both regulation of viral gene transcription and T-cell proliferation. We showed in this report that HBZ interacted with Smad2/3, and enhanced transforming growth factor-β (TGF-β)/Smad transcriptional responses in a p300-dependent manner. The N-terminal LXXLL motif of HBZ was responsible for HBZ-mediated TGF-β signaling activation. In a serial immunoprecipitation assay, HBZ, Smad3, and p300 formed a ternary complex, and the association between Smad3 and p300 was markedly enhanced in the presence of HBZ. In addition, HBZ could overcome the repression of the TGF-β response by Tax. Finally, HBZ expression resulted in enhanced transcription of Pdgfb, Sox4, Ctgf, Foxp3, Runx1, and Tsc22d1 genes and suppression of the Id2 gene; such effects were similar to those by TGF-β. In particular, HBZ induced Foxp3 expression in naive T cells through Smad3-dependent TGF-β signaling. Our results suggest that HBZ, by enhancing TGF-β signaling and Foxp3 expression, enables HTLV-1 to convert infected T cells into regulatory T cells, which is thought to be a critical strategy for virus persistence. [ABSTRACT FROM AUTHOR]

The human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ) gene is encoded by the minus strand of the HTLV-1 provirus and transcribed from the 3' long terminal repeat (LTR). HBZ gene expression not only inhibits the Tax-mediated activation of viral gene transcription through the 5' LTR but also promotes the proliferation of infected cells. However, the HBZ promoter region and the transcriptional regulation of the gene have not been studied. In this study, we characterize the promoters of the spliced version of the HBZ gene (sHBZ) and the unspliced version of the HBZ gene (usHBZ) by luciferase assay. Both promoters were TATA-less and contained initiators and downstream promoter elements. Detailed studies of the promoter for the sHBZ gene showed that Sp1 sites were critical for its activity. The activities of the sHBZ and usHBZ gene promoters were upregulated by Tax through Tax-responsible elements in the 3' LTR. We compared the functions of the proteins derived from the sHBZ and usHBZ transcripts. sHBZ showed a stronger suppression of Tax-mediated transcriptional activation through the 5' LTR than did usHBZ; the level of suppression correlated with the level of protein produced. The expression of sHBZ had a growth-promoting function in a T-cell line, while usHBZ expression did not. This study demonstrates that Sp1 is critical for sHBZ transcription, which accounts for the constitutive expression of the sHBZ gene. Functional differences between sHBZ and usHBZ suggest that the sHBZ gene plays a significant role in the proliferation of infected cells. [ABSTRACT FROM AUTHOR]

Human T cell leukemia virus type 1 (HTLV-1) causes adult T cell leukemia (ATL) in 2-5% of carriers after a long latent period. An HTLV-1 encoded protein, Tax, induces proliferation and inhibits apoptosis, resulting in clonal proliferation of infected cells. However, tax gene expression in ATL cells is disrupted by several mechanisms, including genetic changes in the tax gene and DNA methylation/deletion of the 5' long terminal repeat (LTR). Because Tax is the major target of cytotoxic T-lymphocytes in vivo, loss of Tax expression should enable ATL cells to escape the host immune system. The 5' LTR of HTLV-1 is frequently hypermethylated or deleted in ATL cells, whereas the 3' LTR remains unmethylated and intact, suggesting the involvement of the 3' LTR in leukemogenesis. Here we show that a gene encoded by the minus strand of the HTLV-1 proviral genome, HTLV-1 basic leucine zipper factor (HBZ), is transcribed from 3'-LTR in all ATL cells. Suppression of HBZ gene transcription by short interfering RNA inhibits proliferation of ATL cells. In addition, HBZ gene expression promotes proliferation of a human T cell line. Analyses of T cell lines transfected with mutated HBZ genes showed that HBZ promotes T cell proliferation in its RNA form, whereas HBZ protein suppresses Tax-mediated viral transcription through the 5' LTR. Thus, the single HBZ gene has bimodal functions in two different molecular forms. The growth-promoting activity of HBZ RNA likely plays an important role in oncogenesis by HTLV-1. [ABSTRACT FROM AUTHOR]

Determinants of HIV-1 latency establishment are yet to be elucidated. HIV reservoir comprises a rare fraction of infected cells that can survive host and virus-mediated killing. In vitro reporter models so far offered a feasible means to inspect this population, but with limited capabilities to dissect provirus silencing dynamics. Here, we describe a new HIV reporter model, HIV-Timer of cell kinetics and activity (HIV-Tocky) with dual fluorescence spontaneous shifting to reveal provirus silencing and reactivation dynamics. This unique feature allows, for the first time, identifying two latent populations: a directly latent, and a recently silenced subset, with the latter having integration features suggestive of stable latency. Our proposed model can help address the heterogeneous nature of HIV reservoirs and offers new possibilities for evaluating eradication strategies. A novel in vitro latency model (HIV-Tocky) suggests the multi-layered nature of HIV-1 post-integration latency at which latent proviruses with a history of expression showed features of stable latency in contrary to these lacking a history of expression. [ABSTRACT FROM AUTHOR]

Simple Summary: Gut microbiota is a key regulators of the efficacy of immune checkpoint inhibitor (ICIs). Thus, manipulating microbiota may enhance cancer treatment outcomes. Clostridium butyricum MIYAIRI 588 strain (CBM588) enhances the effects of ICI monotherapy in patients with advanced lung cancer. However, its effect on the outcomes of chemoimmunotherapy combinations in lung cancer remains unknown. We retrospectively analyzed 106 patients with stage IV or recurrent metastatic non-small cell lung cancer (NSCLC) consecutively treated with chemoimmunotherapy combination. CBM588 significantly extended the overall survival in patients with NSCLC receiving chemoimmunotherapy combinations and was associated with overall survival in patients using proton pump inhibitors and/or antibiotics. CBM588-induced manipulation of commensal microbiota has the potential to enhance the efficacy of chemoimmunotherapy combinations. The survival benefit of CBM588 in the tumor-programmed cell death ligand 1 (PD-L1) < 1% cohort was higher than that in the PD-L1 1–49% and PD-L1 ≥ 50% cohorts. Further exploration of the synergy between CBM588 and immunotherapy is warranted. The gut microbiota has emerged as a key regulator of immune checkpoint inhibitor (ICI) efficacy. Therapeutic approaches aimed at manipulating the microbiota through targeted reconstitution to enhance cancer treatment outcomes have garnered considerable attention. A single live microbial biotherapeutic bacterium, Clostridium butyricum MIYAIRI 588 strain (CBM588), has been shown to enhance the effects of ICI monotherapy in patients with advanced lung cancer. However, whether CBM588 affects the outcomes of chemoimmunotherapy combinations in lung cancer remains unknown. We hypothesized that CBM588 augments the effect of chemoimmunotherapy combinations and restores diminished effectiveness in patients with non-small cell lung cancer (NSCLC) receiving dysbiosis-inducing drugs. To validate this hypothesis, we retrospectively analyzed 106 patients with stage IV or recurrent metastatic NSCLC consecutively treated with chemoimmunotherapy combinations. A survival analysis was performed employing univariate and multivariate Cox proportional hazard models with inverse probability of treatment weighting (IPTW) using propensity scores. Forty-five percent of patients received Clostridium butyricum therapy. CBM588 significantly extended overall survival in patients with NSCLC receiving chemoimmunotherapy. The favorable impact of CBM588 on the efficacy of chemoimmunotherapy combinations varied based on tumor-programmed cell death ligand 1 (PD-L1) expression. The survival benefit of CBM588 in the PD-L1 <1% cohort was higher than that in the PD-L1 1–49% and PD-L1 ≥ 50% cohorts. Furthermore, CBM588 was associated with improved overall survival in patients receiving proton pump inhibitors and/or antibiotics. CBM588-induced manipulation of the commensal microbiota holds the potential to enhance the efficacy of chemoimmunotherapy combinations, warranting further exploration of the synergy between CBM588 and immunotherapy. [ABSTRACT FROM AUTHOR]

Human T-cell leukemia virus type-1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL). HTLV-1 carriers have a lifelong asymptomatic balance between infected cells and host antiviral immunity; however, 5–10% of carriers lose this balance and develop ATL. Coinfection with Strongyloides promotes ATL development, suggesting that the immunological status of infected individuals is a determinant of HTLV-1 pathogenicity. As CD4+ T cells play a central role in host immunity, the deregulation of their function and differentiation via HTLV-1 promotes the immune evasion of infected T cells. During ATL development, the accumulation of genetic and epigenetic alterations in key host immunity-related genes further disturbs the immunological balance. Various approaches are available for treating these abnormalities; however, hematopoietic stem cell transplantation is currently the only treatment with the potential to cure ATL. The patient's immune state may contribute to the treatment outcome. Additionally, the activity of the anti-CC chemokine receptor 4 antibody, mogamulizumab, depends on immune function, including antibody-dependent cytotoxicity. In this comprehensive review, we summarize the immunopathogenesis of HTLV-1 infection in ATL and discuss the clinical findings that should be considered when developing treatment strategies for ATL. [ABSTRACT FROM AUTHOR]

An abstract of the research paper titled," The Human T-cell leukemia virus type 1 HTLV-1 bZIP factor enhances TGF-beta signaling through p300 coactivator," is presented.

An abstract of the article "HTLV-1 bZIP Factor-Mediated Dysfunction of Regulatory T Cells in Vivo," by Paola Miyazato and colleagues from 15th International Conference on Human Retroviruses: HTLV and Related Viruses Leuven and Gembloux held in Belgium from June 5-8, 2011 is presented.

An abstract of the article "HTLV-1 bZIP factor perturbs immune response to the pathogens in vivo by inhibiting IFN-gamma production," by Kenji Sugata, Yorifumi Satou, Kisato Nosaka and colleagues, is presented.

An abstract of the research paper titled "HTLV-1 bZIP Factor Induces Systemic Inflammations in Vivo," by Nanae Taguchi, Yorifumi Satou, Koichi Ohshima, Masao Matsuoka is presented.

A recent pandemic of SARS-CoV-2 infection has caused severe health problems and substantially restricted social and economic activities. RT-qPCR plays a vital role in the diagnosis of SARS-CoV-2 infection. The N protein-coding region is widely analyzed in RT-qPCR to diagnose SARS-CoV-2 infection in Japan. We recently encountered two cases of SARS-CoV-2-positive specimens showing atypical amplification curves in the RT-qPCR. We performed whole-genome sequencing of 63 samples (2 showing aberrant RT-qPCR curve and 61 samples infected with SARS-CoV-2 simultaneously in the same area) followed by Phylogenetic tree analysis. We found that the viruses showing abnormal RT-qPCR curves were Delta-type variants of SARS-CoV-2 with a single nucleotide mutation in the probe-binding site. There were no other cases with the same mutation, indicating that the variant had not spread in the area. After searching the database, hundreds of variants were reported globally, and one in Japan contained the same mutation. Phylogenetic analysis showed that the variant was very close to other Delta variants endemic in Japan but quite far from the variants containing the same mutation reported from outside Japan, suggesting sporadic generation of mutant in some domestic areas. These findings propose two key points: i) mutations in the region used for SARS-CoV-2 RT-qPCR can cause abnormal amplification curves, and ii) various mutations can be generated sporadically and unpredictably; therefore, efficient and robust screening systems are needed to promptly monitor the emergence of de novo variants. [ABSTRACT FROM AUTHOR]

Background: Coinfection with human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1) diminishes the value of the CD4+ T-cell count in diagnosing AIDS, and increases the rate of HTLV-1-associated myelopathy. It remains elusive how HIV-1/HTLV-1 coinfection is related to such characteristics. We investigated the mutual effect of HIV-1/HTLV-1 coinfection on their integration sites (ISs) and clonal expansion.Methods: We extracted DNA from longitudinal peripheral blood samples from 7 HIV-1/HTLV-1 coinfected, and 12 HIV-1 and 13 HTLV-1 monoinfected individuals. Proviral loads (PVL) were quantified using real-time polymerase chain reaction (PCR). Viral ISs and clonality were quantified by ligation-mediated PCR followed by high-throughput sequencing.Results: PVL of both HIV-1 and HTLV-1 in coinfected individuals was significantly higher than that of the respective virus in monoinfected individuals. The degree of oligoclonality of both HIV-1- and HTLV-1-infected cells in coinfected individuals was also greater than in monoinfected subjects. ISs of HIV-1 in cases of coinfection were more frequently located in intergenic regions and transcriptionally silent regions, compared with HIV-1 monoinfected individuals.Conclusions: HIV-1/HTLV-1 coinfection makes an impact on the distribution of viral ISs and clonality of virus-infected cells and thus may alter the risks of both HTLV-1- and HIV-1-associated disease. [ABSTRACT FROM AUTHOR]

Human T-cell leukemia virus type 1 (HTLV-1) infects target cells primarily through cell-to-cell routes. Here, we provide evidence that cellular protein M-Sec plays a critical role in this process. When purified and briefly cultured, CD4+ T cells of HTLV-1 carriers, but not of HTLV-1- individuals, expressed M-Sec. The viral protein Tax was revealed to mediate M-Sec induction. Knockdown or pharmacological inhibition of M-Sec reduced viral infection in multiple co-culture conditions. Furthermore, M-Sec knockdown reduced the number of proviral copies in the tissues of a mouse model of HTLV-1 infection. Phenotypically, M-Sec knockdown or inhibition reduced not only plasma membrane protrusions and migratory activity of cells, but also large clusters of Gag, a viral structural protein required for the formation of viral particles. Taken together, these results suggest that M-Sec induced by Tax mediates an efficient cell-to-cell viral infection, which is likely due to enhanced membrane protrusions, cell migration, and the clustering of Gag. Author summary: In the present study, we identified the cellular protein M-Sec as a host factor necessary for de novo infection of human T-cell leukemia virus type 1 (HTLV-1), the causative retrovirus of an aggressive blood cancer known as adult T-cell leukemia/lymphoma. The inhibition or knockdown of M-Sec in infected cells resulted in a reduced viral infection in several culture models and a mouse model. We recently demonstrated a similar role of M-Sec in macrophages infected with another human retrovirus HIV-1, but it has been generally thought that M-Sec is not related to HTLV-1 infection because of the lack of its expression in CD4+ T cells, the major target of HTLV-1. In this study, we revealed that CD4+ T cells of HTLV-1 asymptomatic carriers, but not those of HTLV-1- individuals, expressed M-Sec, and that the viral protein Tax mediated the induction of M-Sec. Thus, M-Sec is a new and useful tool for further understanding the process of HTLV-1 transmission. [ABSTRACT FROM AUTHOR]

Background: Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4+ T-cells caused by human T-cell leukemia virus type 1 (HTLV-1). The HTLV-1 bZIP factor (HBZ) gene, which is encoded by the minus strand of the viral genome, is expressed as an antisense transcript in all ATL cases. By using yeast two-hybrid screening, we identified activating transcription factor 3 (ATF3) as an HBZ-interacting protein. ATF3 has been reported to be expressed in ATL cells, but its biological significance is not known. Results: Immunoprecipitation analysis confirmed that ATF3 interacts with HBZ. Expression of ATF3 was upregulated in ATL cell lines and fresh ATL cases. Reporter assay revealed that ATF3 could interfere with the HTLV-1 Tax's transactivation of the 5' proviral long terminal repeat (LTR), doing so by affecting the ATF/CRE site, as well as HBZ. Suppressing ATF3 expression inhibited proliferation and strongly reduced the viability of ATL cells. As mechanisms of growth-promoting activity of ATF3, comparative expression profiling of ATF3 knockdown cells identified candidate genes that are critical for the cell cycle and cell death, including cell division cycle 2 (CDC2) and cyclin E2. ATF3 also enhanced p53 transcriptional activity, but this activity was suppressed by HBZ. Conclusions: Thus, ATF3 expression has positive and negative effects on the proliferation and survival of ATL cells. HBZ impedes its negative effects, leaving ATF3 to promote proliferation of ATL cells via mechanisms including upregulation of CDC2 and cyclin E2. Both HBZ and ATF3 suppress Tax expression, which enables infected cells to escape the host immune system. [ABSTRACT FROM AUTHOR]

Background: Recently, human T-cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ), encoded from a minus strand mRNA was discovered and was suggested to play an important role in adult T cell leukemia (ATL) development. However, there have been no reports on the role of HBZ in patients with HTLV-1 associated inflammatory diseases. Results: We quantified the HBZ and tax mRNA expression levels in peripheral blood from 56 HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients, 10 ATL patients, 38 healthy asymptomatic carriers (HCs) and 20 normal uninfected controls, as well as human leukemic T-cell lines and HTLV-1-infected T-cell lines, and the data were correlated with clinical parameters. The spliced HBZ gene was transcribed in all HTLV-1-infected individuals examined, whereas tax mRNA was not transcribed in significant numbers of subjects in the same groups. Although the amount of HBZ mRNA expression was highest in ATL, medium in HAM/TSP, and lowest in HCs, with statistical significance, neither tax nor the HBZ mRNA expression per HTLV- 1-infected cell differed significantly between each clinical group. The HTLV-1 HBZ, but not tax mRNA load, positively correlated with disease severity and with neopterin concentration in the cerebrospinal fluid of HAM/TSP patients. Furthermore, HBZ mRNA expression per HTLV-1- infected cell was decreased after successful immunomodulatory treatment for HAM/TSP. Conclusion: These findings suggest that in vivo expression of HBZ plays a role in HAM/TSP pathogenesis. [ABSTRACT FROM AUTHOR]

Bovine leukemia virus (BLV) is an oncogenic retrovirus which induces malignant lymphoma termed enzootic bovine leukosis (EBL) after a long incubation period. Insertion sites of the BLV proviral genome as well as the associations between disease progression and polymorphisms of the virus and host genome are not fully understood. To characterize the biological coherence between virus and host, we developed a DNA-capture-seq approach, in which DNA probes were used to efficiently enrich target sequence reads from the next-generation sequencing (NGS) library. In addition, enriched reads can also be analyzed for detection of proviral integration sites and clonal expansion of infected cells since the reads include chimeric reads of the host and proviral genomes. To validate this DNA-capture-seq approach, a persistently BLV-infected fetal lamb kidney cell line (FLK-BLV), four EBL tumor samples and four non-EBL blood samples were analyzed to identify BLV integration sites. The results showed efficient enrichment of target sequence reads and oligoclonal integrations of the BLV proviral genome in the FLK-BLV cell line. Moreover, three out of four EBL tumor samples displayed multiple integration sites of the BLV proviral genome, while one sample displayed a single integration site. In this study, we found the evidence for the first time that the integrated provirus defective at the 5′ end was present in the persistent lymphocytosis cattle. The efficient and sensitive identification of BLV variability, integration sites and clonal expansion described in this study provide support for use of this innovative tool for understanding the detailed mechanisms of BLV infection during the course of disease progression. [ABSTRACT FROM AUTHOR]

T-cells play key roles in immunity to COVID-19 as well as the development of severe disease. T-cell immunity to COVID-19 is mediated through differentiated CD4+ T-cells and cytotoxic CD8+ T-cells, although their differentiation is often atypical and ambiguous in COVID-19 and single cell dynamics of key genes need to be characterized. Notably, T-cells are dysregulated in severe COVID-19 patients, although their molecular features are still yet to be fully revealed. Importantly, it is not clear which T-cell activities are beneficial and protective and which ones can contribute to the development of severe COVID-19. In this article, we examine the latest evidence and discuss the key features of T-cell responses in COVID-19, showing how T-cells are dysregulated in severe COVID-19 patients. Particularly, we highlight the impairment of FOXP3 induction in CD4+ T-cells and how the impaired FOXP3 expression can lead to the differentiation of abnormally activated (hyperactivated) T-cells and the dysregulated T-cell responses in severe patients. Furthermore, we characterise the feature of hyperactivated T-cells, showing their potential contribution to T-cell dysregulation and immune-mediated tissue destruction (immunopathology) in COVID-19. [ABSTRACT FROM AUTHOR]

Background: Human T cell leukaemia virus type 1 (HTLV-1) is a retrovirus associated with human diseases such as adult T-cell leukaemia/lymphoma and HTLV-1 associated myelopathy/tropical spastic paraparesis. In contrast to another human retrovirus, human immunodeficiency virus type 1 (HIV-1), HTLV-1 persists in the host not via vigorous virus production but mainly via proliferation and/or long-term survival in the form of silent proviruses in infected host cells. As a result, HTLV-1-infected cells rarely produce virus particles in vivo even without anti-retroviral treatment. That should be an advantage for the virus to escape from the host immune surveillance by minimizing the expression of viral antigens in host cells. However, why HIV-1 and HTLV-1 behave so differently during natural infection is not fully understood. Results: We performed cap analysis of gene expression (CAGE) using total RNAs and nascent, chromatin-associated, RNAs in the nucleus and found that HTLV-1 RNAs were processed post-transcriptionally in infected cells. RNA processing was evident for the sense viral transcripts but not the anti-sense ones. We also found a higher proportion of CG di-nucleotides in proviral sequences of HTLV-1-infected cells, when compared to the HIV-1 genomic sequence. It has been reported recently that CG dinucleotide content of viral sequence is associated with susceptibility to the antiviral ZC3HAV1 (ZAP), suggesting the involvement of this protein in the regulation of HTLV-1 transcripts. To analyse the effect of ZAP on HTLV-1 transcripts, we over-expressed it in HTLV-1-infected cells. We found there was a dose-dependent reduction in virus production with ZAP expression. We further knocked down endogenous ZAP with two independent targeting siRNAs and observed a significant increase in virus production in the culture supernatant. Other delta-type retroviruses such as simian T-cell leukaemia virus and bovine leukaemia virus, also contain high CG-dinucleotide contents in their viral genomes, suggesting that ZAP-mediated suppression of viral transcripts might be a common feature of delta-type retroviruses, which cause minimal viremia in their natural hosts. Conclusions: The post-transcriptional regulatory mechanism involving ZAP might allow HTLV-1 to maintain a delicate balance required for prolonged survival in infected individuals. [ABSTRACT FROM AUTHOR]

Fibrocytes (fibroblastic leukocytes) are recently identified as unique hematopoietic cells with features of both macrophages and fibroblasts. Fibrocytes are known to contribute to the remodeling or fibrosis of various injured tissues. However, their role in viral infection is not fully understood. In this study, we show that differentiated fibrocytes are phenotypically distinguishable from macrophages but can be infected with HIV-1. Importantly, fibrocytes exhibited persistently infected cell-like phenotypes, the degree of which was more apparent than macrophages. The infected fibrocytes produced replication-competent HIV-1, but expressed HIV-1 mRNA at low levels and strongly resisted HIV-1-induced cell death, which enabled them to support an extremely long-term HIV-1 production at low but steady levels. More importantly, our results suggested that fibrocytes were susceptible to HIV-1 regardless of their differentiation state, in contrast to the fact that monocytes become susceptible to HIV-1 after the differentiation into macrophages. Our findings indicate that fibrocytes are the previously unreported HIV-1 host cells, and they suggest the importance of considering fibrocytes as one of the long-lived persistently infected cells for curing HIV-1. [ABSTRACT FROM AUTHOR]

The precise role of viral protein R (Vpr), an HIV-1-encoded protein, during HIV-1 infection and its contribution to the development of AIDS remain unclear. Previous reports have shown that Vpr has the ability to cause G2 cell cycle arrest and apoptosis in HIV-1-infected cells in vitro. In addition, vpr is highly conserved in transmitted/founder HIV-1s and in all primate lentiviruses, which are evolutionarily related to HIV-1. Although these findings suggest an important role of Vpr in HIV-1 pathogenesis, its direct evidence in vivo has not been shown. Here, by using a human hematopoietic stem cell-transplanted humanized mouse model, we demonstrated that Vpr causes G2 cell cycle arrest and apoptosis predominantly in proliferating CCR5+ CD4+ T cells, which mainly consist of regulatory CD4+ T cells (Tregs), resulting in Treg depletion and enhanced virus production during acute infection. The Vpr-dependent enhancement of virus replication and Treg depletion is observed in CCR5-tropic but not CXCR4-tropic HIV-1-infected mice, suggesting that these effects are dependent on the coreceptor usage by HIV-1. Immune activation was observed in CCR5-tropic wild-type but not in vpr-deficient HIV-1-infected humanized mice. When humanized mice were treated with denileukin diftitox (DD), to deplete Tregs, DD-treated humanized mice showed massive activation/proliferation of memory T cells compared to the untreated group. This activation/proliferation enhanced CCR5 expression in memory CD4+ T cells and rendered them more susceptible to CCR5-tropic wild-type HIV-1 infection than to vpr-deficient virus. Taken together, these results suggest that Vpr takes advantage of proliferating CCR5+ CD4+ T cells for enhancing viremia of CCR5-tropic HIV-1. Because Tregs exist in a higher cycling state than other T cell subsets, Tregs appear to be more vulnerable to exploitation by Vpr during acute HIV-1 infection. [ABSTRACT FROM AUTHOR]

Erratum to: Clonality of HIV-1- and HTLV-1-Infected Cells in Naturally Coinfected Individuals In the original publication of this manuscript "Clonality of HIV-1- and HTLV-1-Infected Cells in Naturally Coinfected Individuals" by Katusya et al. [J Infect Dis, April 2021. https://doi.org/10.1093/jid/jiab202], revised Figures 1, 3A, and 3B were provided during production but were not replaced before final publication. Mentions of virus-1, HIV and HTLV have also been updated in this article to virus type 1, HIV-1, and HTLV-1 respectively. [Extracted from the article]

Regardless of recent advances in the development of anti-retroviral drugs, it is still extremely difficult to eradicate HIV-1 from infected individuals. The characterization of the HIV-1 provirus, a type of viral reservoir, with a high resolution is key to HIV-1 cure research. Here, we demonstrate that DNA-capture-seq is a powerful tool to obtain comprehensive information on the HIV-1 provirus. We use biotinylated DNA probes targeting the entire HIV-1 sequence to capture fragments containing HIV-1 sequences from DNA-seq libraries prepared for high throughput sequencing. We demonstrate that the protocol provided the entire proviral sequence from the beginning of the 5′ LTR to the end of the 3′ LTR. Since HIV-1 DNA-probes can hybridize not only viral fragments but also virus-host chimeric ones, the viral integration site information can also be obtained. We verify the efficiency of the protocol by using latently infected cell lines, such as ACH-2 and J1.1, and newly generated ones. The results reveal that the 2 new clones that we analyse harbour one copy of replication-competent provirus, suggesting that latency is not caused by genetic mutations or deletions of the provirus. In conclusion, HIV-1 DNA-capture-seq is a powerful tool to characterize the HIV-1 provirus at a single nucleotide resolution and therefore might be useful for various experiments aiming for an HIV-1 cure. [ABSTRACT FROM AUTHOR]

An abstract of the article "APOBEC3G Generates Nonsense Mutations in Human T-Cell Leukemia Virus Type 1 Proviral Genomes In Vivo," by Jun Fan, Guangyong Ma, Kisato Nosaka, Junko Tanabe, Yorifumi Satou, Atsushi Koito, Simon Wain-Hobson, Jean-Pierre Vartanian and Masao Matsuoka is presented.