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HTLV-1 type-A rarely causes lung disease in humans, whereas HTLV-1 type-C is more frequently associated with respiratory failure and premature death. We investigated the genetic basis of HTLV-1C morbidity by constructing a chimeric HTLV-1A/C oI-L encompassing the highly divergent type C orf-I. We demonstrate that systemic infectivity of HTLV-1A and HTLV-1A/C oI-L is equivalent in macaques, but viral expression in lungs is significantly higher in HTLV-1A/C oI-L infection. In addition, bronchoalveolar-lavage immune cell dynamics differs greatly with neutrophils and monocytes producing TNF-α in HTLV-1A/C oI-L , but producing IL-10 in HTLV-1A infection. Animals infected with HTLV-1A/C oI-L develops bronchiectasis at 10 months from infection, but at the same timepoint those infected with HTLV-1A do not. HTLV-1A/C oI-L expressed a 16 kDa fusion protein (p16C) via a doubly spliced, Rex-orf-IC, mRNA able to shield T-cells from efferocytosis, a monocyte function that mitigates inflammation via clearance of apoptotic cells. The Rex-orf-IC mRNA is expressed as more frequent in the lung of HTLV-1A/C oI-L than HTLV-1A infected animals. Since defective efferocytosis is associated with lung obstructive pathologies, the data raise the hypothesis that p16C may contribute to the lung morbidity observed in HTLV-1C infection. HTLV-1 type-C causes more severe disease than type-A, but the underlying reason is unclear. Here the authors show in a macaque model how type-C orf-I affects lung pathogenesis and the immune response to HTLV-1, providing a model to test viral targets for disease prevention.

Paradigm shifts throughout the history of microbiology have typically been ignored, or met with skepticism and resistance, by the scientific community. This has been especially true in the field of virology, where the discovery of a “contagium vivum fluidum”, or infectious fluid remaining after excluding bacteria by filtration, was initially ignored because it did not coincide with the established view of microorganisms. Subsequent studies on such infectious agents, eventually termed “viruses”, were met with skepticism. However, after an abundance of proof accumulated, viruses were eventually acknowledged as defined microbiological entities. Next, the proposed role of viruses in oncogenesis in animals was disputed, as was the unique mechanism of genome replication by reverse transcription of RNA by the retroviruses. This same pattern of skepticism holds true for the prediction of the existence of retroviral “antisense” transcripts and genes. From the time of their discovery, it was thought that retroviruses encoded proteins on only one strand of proviral DNA. However, in 1988, it was predicted that human immunodeficiency virus type 1 (HIV-1), and other retroviruses, express an antisense protein encoded on the DNA strand opposite that encoding the known viral proteins. Confirmation came quickly with the characterization of the antisense protein, HBZ, of the human T-cell leukemia virus type 1 (HTLV-1), and the finding that both the protein and its antisense mRNA transcript play key roles in viral replication and pathogenesis. However, acceptance of the existence, and potential importance, of a corresponding antisense transcript and protein (ASP) in HIV-1 infection and pathogenesis has lagged, despite gradually accumulating theoretical and experimental evidence. The most striking theoretical evidence is the finding that asp is highly conserved in group M viruses and correlates exclusively with subtypes, or clades, responsible for the AIDS pandemic. This review outlines the history of the major shifts in thought pertaining to the nature and characteristics of viruses, and in particular retroviruses, and details the development of the hypothesis that retroviral antisense transcripts and genes exist. We conclude that there is a need to accelerate studies on ASP, and its transcript(s), with the view that both may be important, and overlooked, targets in anti-HIV therapeutic and vaccine strategies.

Adult T‐cell leukemia‐lymphoma (ATL) is caused by human T‐cell leukemia virus type 1 (HTLV‐1) infection. Among HTLV‐1 encoded genes, HTLV‐1 bZIP factor (HBZ) and tax are critical for the leukemogenesis of ATL. Adult T‐cell leukemia‐lymphoma needs a long latent period before onset, indicating that both viral genes and alterations (genetic and epigenetic) of the host genome play important roles for leukemogenesis. Viral genes influence genetic and epigenetic changes of the host genome, indicating that the virus is of primary importance in leukemogenesis. HBZ is expressed in all ATL cases, whereas Tax expression is heterogeneous among ATL cases. Different patterns of viral gene expression in tumors are also observed for Epstein‐Barr virus. We propose three subtypes of ATL cases based on Tax expression: high, intermittent, and lost expression. HBZ is detected in all ATL cases. Approximately 25% of all ATL cases lost Tax expression at infection of HTLV‐1, indicating that HBZ is the only viral gene responsible for leukemogenesis in addition to genetic and epigenetic changes of the host genes in these ATL cases. The host immune responses to Tax are also implicated in the heterogeneity of ATL. Thus, ATL is a heterogeneous disease in terms of its viral gene expression, which is important for pathogenesis of this intractable lymphomatous neoplasm. In this review, we describe the heterogeneity of adult T‐cell leukemia‐lymphoma (ATL) in regard to viral gene expression, and propose three subtypes of ATL. These findings lead to an understanding of pathogenesis by human T‐cell leukemia virus type 1 and new therapeutic strategies for ATL.

Key Points Retroviruses exploit a vast array of host cellular proteins during their replication. Every step in the viral life cycle requires a distinct set of these host factors. Host factors provide attractive targets for therapeutic intervention. The cellular genes encoding these factors would not rapidly mutate to produce drug-resistant variants. Nonspecific inhibition of host machinery, however, could prove toxic. Retroviruses often use transport systems that are involved in the movement of cellular cargoes using cytoskeletal motors, or in vesicle trafficking. Different retroviruses use different sets of host factors. Viruses often use redundant pathways, or use alternative pathways present in particular cell types. Sometimes the viruses disrupt a host process or molecular machine for the purposes of virus replication. For example, the ESCRT machinery, which is normally involved in protein sorting to the endosome, is relocated to the plasma membrane by enveloped viruses and exploited for their budding and release. Genomic screens indicate that the total number of host factors needed by viruses is enormous and that current information about these factors and their roles in virus replication is still incomplete. Retroviruses, which encode fewer than ten genes, need to interact with cellular proteins for virtually all aspects of their replication cycle. In this Review, Stephen Goff describes how host factors and cellular pathways are exploited at each stage of the retrovirus lifecycle. Throughout, comparisons are drawn between HIV and other retroviruses. Retroviruses make a long and complex journey from outside the cell to the nucleus in the early stages of infection, and then an equally long journey back out again in the late stages of infection. Ongoing efforts are identifying an enormous array of cellular proteins that are used by the viruses in the course of their travels. These host factors are potential new targets for therapeutic intervention.

Human T cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases. The HTLV-1 bZIP factor (HBZ) gene is constantly expressed in HTLV-1 infected cells and ATL cells. HBZ protein suppresses transcription of the tax gene through blocking the LTR recruitment of not only ATF/CREB factors but also CBP/p300. HBZ promotes transcription of Foxp3, CCR4, and T-cell immunoreceptor with Ig and ITIM domains (TIGIT). Thus, HBZ is critical for the immunophenotype of infected cells and ATL cells. HBZ also functions in its RNA form. HBZ RNA suppresses apoptosis and promotes proliferation of T cells. Since HBZ RNA is not recognized by cytotoxic T cells, HTLV-1 has a clever strategy for avoiding immune detection. HBZ plays central roles in maintaining infected T cells in vivo and determining their immunophenotype.

Non-human primates (NHP) are an important source of viruses that can spillover to humans and, after adaptation, spread through the host population. Whereas HIV-1 and HTLV-1 emerged as retroviral pathogens in humans, a unique class of retroviruses called foamy viruses (FV) with zoonotic potential are occasionally detected in bushmeat hunters or zookeepers. Various FVs are endemic in numerous mammalian natural hosts, such as primates, felines, bovines, and equines, and other animals, but not in humans. They are apathogenic, and significant differences exist between the viral life cycles of FV and other retroviruses. Importantly, FVs replicate in the presence of many well-defined retroviral restriction factors such as TRIM5α, BST2 (Tetherin), MX2, and APOBEC3 (A3). While the interaction of A3s with HIV-1 is well studied, the escape mechanisms of FVs from restriction by A3 is much less explored. Here we review the current knowledge of FV biology, host restriction factors, and FV–host interactions with an emphasis on the consequences of FV regulatory protein Bet binding to A3s and outline crucial open questions for future studies.

Human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus that causes malignant and inflammatory diseases in ∼10% of infected people. A typical host has between 104 and 105 clones of HTLV-1–infected T lymphocytes, each clone distinguished by the genomic integration site of the single-copy HTLV-1 provirus. The HTLV-1 bZIP (HBZ) factor gene is constitutively expressed from the minus strand of the provirus, whereas plus-strand expression, required for viral propagation to uninfected cells, is suppressed or intermittent in vivo, allowing escape from host immune surveillance. It remains unknown what regulates this pattern of proviral transcription and latency. Here, we show that CTCF, a key regulator of chromatin structure and function, binds to the provirus at a sharp border in epigenetic modifications in the pX region of the HTLV-1 provirus in T cells naturally infected with HTLV-1. CTCF is a zinc-finger protein that binds to an insulator region in genomic DNA and plays a fundamental role in controlling higher order chromatin structure and gene expression in vertebrate cells.We show that CTCF bound to HTLV-1 acts as an enhancer blocker, regulates HTLV-1 mRNA splicing, and forms long-distance interactions with flanking host chromatin. CTCF-binding sites (CTCF-BSs) have been propagated throughout the genome by transposons in certain primate lineages, but CTCF binding has not previously been described in present-day exogenous retroviruses. The presence of an ectopic CTCF-BS introduced by the retrovirus in tens of thousands of genomic locations has the potential to cause widespread abnormalities in host cell chromatin structure and gene expression.

Key Points c-Cbl is a multidomain signalling protein that was first identified as part of an oncogenic mouse retrovirus. Other mammalian homologues (Cbl-b and Cbl-3), and Cbl proteins in Drosophila melanogaster and Caenorhabditis elegans have since been identified. Loss-of-function mutations in Cbl from C. elegans (known as SLI-1) restore signalling from a weakly active LET-23 receptor tyrosine kinase (RTK), a finding that defined Cbl proteins as negative regulators of RTKs. All Cbl proteins have a unique tyrosine-kinase-binding (TKB) domain that recognizes phosphorylated tyrosines on activated RTKs, and a RING finger domain that recruits ubiquitin-conjugating enzymes. These two domains are primarily responsible for Cbl proteins functioning as ubiquitin protein ligases that direct multi-ubiquitylation and downregulation of RTKs. c-Cbl can also target and negatively regulate non-receptor tyrosine kinases such as Syk and ZAP-70, but whether the mechanism involves E3 activity remains uncertain. Cbl proteins have additional regions that mediate binding to numerous proteins that contain Src homology region 2 and 3 (SH2 and SH3) domains and 14-3-3 proteins. These regions are associated with the formation of protein complexes at the site of activated tyrosine kinases, some of which are involved in bone resorption, glucose uptake and cell spreading. Cbl proteins can be made oncogenic by overexpressing the TKB domain alone (v-Cbl) or by deleting amino acids within an α-helix in a small domain that links the TKB domain to the RING finger. These mutations disrupt TKB domain interactions with the linker α-helix and abolish E3 activity. Loss of E3 activity alone is insufficient for transformation as not all mutations that abolish RTK multi-ubiquitylation are transforming. Transformation also requires an undefined deregulation of TKB domain function, which results in the constitutive activation of RTKs. c-Cbl- and Cbl-b-deficient mice show enhanced signalling in thymocytes and peripheral T cells, respectively. In both c-Cbl and Cbl-b mutant mice, T-cell-receptor responses are uncoupled from a requirement for co-receptor stimulation. Responses to extracellular stimuli are often transduced from cell-surface receptors to protein tyrosine kinases which, when activated, initiate the formation of protein complexes that transmit signals throughout the cell. A prominent component of these complexes is the product of the proto-oncogene c- Cbl , which specifically targets activated protein tyrosine kinases and regulates their signalling. How, then, does this multidomain protein shape the responses generated by these signalling complexes?

Growing evidence suggests that the modulation of intrinsic termination and readthrough of transcription is more widespread than previously appreciated. For small RNAs, proper termination plays a critical role in their regulatory function. The regulatory function of many bacterial small RNAs (sRNAs) requires the binding of the RNA chaperone Hfq to the 3′ portion of the sRNA intrinsic terminator, and therefore sRNA signaling might be regulated by modulating its terminator. Here, using a multicopy screen developed with the terminator of sRNA SgrS, we identified an sRNA gene ( cyaR ) and three protein-coding genes ( cspD , ygjH , and rof ) that attenuate SgrS termination in Escherichia coli . Analyses of CyaR and YgjH, a putative tRNA binding protein, suggested that the CyaR activity was indirect and the effect of YgjH was moderate. Overproduction of the protein attenuators CspD and Rof resulted in more frequent readthrough at terminators of SgrS and two other sRNAs, and regulation by SgrS of target mRNAs was reduced. The effect of Rof, a known inhibitor of Rho, was mimicked by bicyclomycin or by a rho mutant, suggesting an unexpected role for Rho in sRNA termination. CspD, a member of the cold shock protein family, bound both terminated and readthrough transcripts, stabilizing them and attenuating termination. By RNA sequencing analysis of the CspD overexpression strain, we found global effects of CspD on gene expression across some termination sites. We further demonstrated effects of endogenous CspD under slow growth conditions where cspD is highly expressed. These findings provided evidence of changes in the efficiency of intrinsic termination, confirming this as an additional layer of the regulation of sRNA signaling. IMPORTANCE Growing evidence suggests that the modulation of intrinsic termination and readthrough of transcription is more widespread than previously appreciated. For small RNAs, proper termination plays a critical role in their regulatory function. Here, we present a multicopy screen approach to identify factors that attenuate small RNA termination and therefore abrogate signaling dependent on the small RNA. This study highlights a new aspect of regulation of small RNA signaling as well as the modulation of intrinsic termination.

Background Human T cell lymphotropic virus type 1 (HTLV-1) is the etiological agent of a severe form of neoplasia designated Adult T cell Leukaemia (ATL). It is widely accepted that the viral transactivator Tax-1 is the major viral product involved in the onset, but not in the maintenance, of neoplastic phenotype, as only 30–40% of ATL cells express Tax-1. It has been recently demonstrated that HBZ (HTLV-1 bZIP factor), a protein encoded by the minus strand of HTLV-1 genome, constantly expressed in infected cells and in ATL tumor cells, is also involved in the pathogenesis of leukaemia. The full role played by HBZ in oncogenesis is not clarified in detail also because of the limited availability of tools to assess quantitative expression, subcellular location and interaction of HBZ with host factors in ATL. Results By the use of the first reported monoclonal antibody against HBZ, 4D4-F3, generated in our laboratory it has been possible to carefully assess for the first time the above parameters in HTLV-1 chronically infected cells and, most importantly, in fresh leukemic cells from patients. Endogenous HBZ is expressed in speckle-like structures localized in the nucleus. The calculated number of endogenous HBZ molecules varies between 17.461 and 39.615 molecules per cell, 20- to 50-fold less than the amount expressed in HBZ transfected cells used by most investigators to assess the expression, function and subcellular localization of the viral protein. HBZ interacts in vivo with p300 and JunD and co-localizes only partially, and depending on the amount of expressed HBZ, not only with p300 and JunD but also with CBP and CREB2. Conclusions The possibility to study endogenous HBZ in detail may significantly contribute to a better delineation of the role of HBZ during HTLV-1 infection and cellular transformation.