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Results for “Enhancer Elements, Genetic”

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PubMed2000

Genetic analysis of bristle loss in hybrids between Drosophila melanogaster and D. simulans provides evidence for divergence of cis-regulatory sequences in the achaete-scute gene complex.

The two closely related species of Drosophila, D. melanogaster and D. simulans, display an identical bristle pattern on the notum, but hybrids between the two are lacking a variable number of bristles. We show that the loss is temperature-dependent and provide evidence for two periods of temperature sensitivity. A first period of heat sensitivity occurs during larval development and corresponds to the time when the prepattern of expression of genes whose products activate achaete-scute in the proneural clusters preceding bristle precursor formation is established. A second period of cold sensitivity corresponds to the time of emergence of the bristle precursor cells and the maintenance of their neural fate, a process requiring high levels of Achaete-Scute. Expression of achaete-scute at these two critical periods depends on cis-regulatory elements of the achaete-scute complex (AS-C). The differences between males, which have only one copy of the X-linked AS-C from D. simulans, and females, which have copies from both parental species, are compared, together with the effects of crossing in different rearrangements of the D. melanogaster AS-C that delete regulatory and/or coding sequences. We provide evidence that bristle loss in the hybrids may result from a decrease in the level of transcription at the AS-C and argue that interaction between trans-acting factors and cis-regulatory elements within the AS-C has diverged between the two species.

Animals↗

PubMed1993

Genetic heterogeneity of oncogenic human papillomavirus type 5 (HPV5) and phylogeny of HPV5 variants associated with epidermodysplasia verruciformis.

Variants of oncogenic human papillomavirus type 5 (HPV5), specifically associated with epidermodysplasia verruciformis, were recognized on the basis of the genetic heterogeneity of the E6 open reading frame (ORF). To further evaluate the genetic heterogeneity of HPV5, we sequenced the long control region (LCR), the E7 ORF, and the terminal parts of the E2 ORF of five previously characterized HPV5 variants and compared the data with the published HPV5a1 and HPV5b sequences. Alignment of the variants showed 140 (7.6%) variable nucleotides of 1,854 sequenced. Nucleotide substitution rates varied from 3.6% in the E7 ORF to 11% in the E6 ORF. By sequencing the variable region encompassing the LCR 3' part and the E6 ORF of isolates from six additional epidermodysplasia verruciformis patients, we identified three new variants and three already known variants, indicating the stability of HPV5 variants. This stability was further demonstrated by the identity of isolates obtained years later from benign and malignant lesions of three patients. Phylogenetic analysis of the 10 HPV5 variants distributed them into three groups, tentatively defining subtypes a, b, and c. The phylogenetic grouping shows no geographical dependence, a fact that may be related to the host restriction that characterizes HPV5 infections. No differences in the enhancer potential of the LCR or in the transactivating properties of the E2 protein assayed in vitro were observed among HPV5 variants. Whether HPV5 variants possess distinct biological properties in vivo remains to be determined.

Base Sequence↗

PubMed1993

Cyclic AMP-mediated augmentation of thrombomodulin gene expression: cell type-dependent usage of control regions.

We reported that a cell surface thrombin receptor, thrombomodulin (TM), was regulated by cyclic AMP in fibroblasts and in parietal endoderm-like cells derived from F9 embryonal carcinoma cells. In this paper, the genetic basis for augmentation of TM expression by cyclic AMP was studied in F9 and BALB/3T3 cells. Transient expression assays were performed with plasmid constructs containing various 5' flanking sequences of the TM gene and a reporter gene, chloramphenicol acetyltransferase (CAT). Two regulatory DNA regions, the proximal (-411 to -50) and the distal (-1026 to -850), were located. Interplay of the two regions was suggested using a heterologous thymidine kinase promoter in differentiated F9 cells. Both proximal and distal regions contributed to cyclic AMP-dependent augmentation of CAT expression in differentiated F9 cells, whereas only the proximal region was functional in BALB/3T3 cells. The two cell types responded differently also to a protein synthesis inhibitor, cycloheximide, with respect to TM message accumulation. In BALB/3T3 cells TM message accumulation was refractory to the inhibitor in contrast to that of differentiated F9 cells, which was only partially so. We propose that there are at least two separate genomic DNA regions that regulate cyclic AMP-dependent TM gene expression and that their functions are cell type dependent.

3T3 Cells↗

PubMed2005

Downregulation of internal enhancer activity contributes to abnormally low immunoglobulin expression in the MedB-1 mediastinal B-cell lymphoma cell line.

Primary mediastinal B-cell lymphoma (PMBL) is a highly aggressive tumour with a unique pattern of clinical, morphological, immunological and genetic features distinct from other diffuse large B-cell lymphomas. PMBLs are characterized by a mature B-cell phenotype, but they typically lack immunoglobulin (Ig) gene expression. The PMBL cell line MedB-1 shares many characteristic properties of the primary tumour, including low-level Ig production despite a functionally rearranged IgVH gene and absence of 'crippling' mutations. In this study, a search was undertaken for reasons for downregulated Ig expression. Similar levels of the B-cell-specific transcription factors BOB.1/OBF.1 and PU.1 were found in MedB-1 cells to those in the Ig-producing UM-1 lymphoblastoid cell line. However, MedB-1 lacked the Oct2 transcription factor. Reporter assays showed that Ig-type promoters were active in MedB-1 cells. In contrast, activity of the intronic heavy chain enhancer was dramatically reduced. Ectopic expression of Oct2 was able partially to restore enhancer activity but transcription from the endogenous IgVH gene could not be rescued. Therefore, the role of epigenetic factors in the downregulation of Ig was investigated. Methylated histone 3 lysine 9, a reliable marker of chromatin silencing, was not detected in MedB-1 promoter and enhancer regions. Inhibition of DNA methyltransferase and of histone deacetylases also did not reactivate Ig production. These data suggest the existence of alternative mechanisms of Ig inhibition in MedB-1 cells, different from chromatin silencing and the lack of Oct2.

DNA Methylation↗

PubMed1999

Kinetic analysis of segmentation gene interactions in Drosophila embryos.

A major challenge for developmental biologists in coming years will be to place the vast number of newly identified genes into precisely ordered genetic and molecular pathways. This will require efficient methods to determine which genes interact directly and indirectly. One of the most comprehensive pathways currently under study is the genetic hierarchy that controls Drosophila segmentation. Yet, many of the potential interactions within this pathway remain untested or unverified. Here, we look at one of the best-characterized components of this pathway, the homeodomain-containing transcription factor Fushi tarazu (Ftz), and analyze the response kinetics of known and putative target genes. This is achieved by providing a brief pulse of Ftz expression and measuring the time required for genes to respond. The time required for Ftz to bind and regulate its own enhancer, a well-documented interaction, is used as a standard for other direct interactions. Surprisingly, we find that both positively and negatively regulated target genes respond to Ftz with the same kinetics as autoregulation. The rate-limiting step between successive interactions (<10 minutes) is the time required for regulatory proteins to either enter or be cleared from the nucleus, indicating that protein synthesis and degradation rates are closely matched for all of the proteins studied. The matching of these two processes is likely important for the rapid and synchronous progression from one class of segmentation genes to the next. In total, 11 putative Ftz target genes are analyzed, and the data provide a substantially revised view of Ftz roles and activities within the segmentation hierarchy.

Animals↗

PubMed2002

aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation.

Presenilins are components of the gamma-secretase protein complex that mediates intramembranous cleavage of betaAPP and Notch proteins. A C. elegans genetic screen revealed two genes, aph-1 and pen-2, encoding multipass transmembrane proteins, that interact strongly with sel-12/presenilin and aph-2/nicastrin. Human aph-1 and pen-2 partially rescue the C. elegans mutant phenotypes, demonstrating conserved functions. The human genes must be provided together to rescue the mutant phenotypes, and the inclusion of presenilin-1 improves rescue, suggesting that they interact closely with each other and with presenilin. RNAi-mediated inactivation of aph-1, pen-2, or nicastrin in cultured Drosophila cells reduces gamma-secretase cleavage of betaAPP and Notch substrates and reduces the levels of processed presenilin. aph-1 and pen-2, like nicastrin, are required for the activity and accumulation of gamma-secretase.

Alzheimer Disease↗

PubMed2005

Expression of the mouse Fgf15 gene is directly initiated by Sonic hedgehog signaling in the diencephalon and midbrain.

Sonic hedgehog (Shh) is a secreted molecule that is thought to regulate tissue growth and patterning in vertebrate embryos. Although it has been reported that Gli transcription factors mediate Shh signaling to the nucleus, little is known about developmental target genes of Gli. In the previous genetic study, we showed that Shh is required for Fgf15 expression in the diencephalon and midbrain. Here, we examined whether Fgf15 is a direct target of Shh signaling through Gli. Shh was expressed in the midline cells and Fgf15 in the medial region of the diencephalon/midbrain by the seven-somite stage. The Fgf15 expression domain coincided with that of Gli1 and overlapped with that of Gli2 at this stage. Fgf15 expression in the diencephalon/midbrain was greatly reduced in the seven-somite Shh mutant embryos. Transgenic analysis showed that the 3.6-kb 5'-flanking region of the Fgf15 gene is sufficient for induction of Fgf15 in the medial/ventral diencephalon/midbrain. Luciferase assay showed that the 3.6-kb Fgf15 enhancer/promoter was activated by Gli2. A Gli-binding site was located 1 kb upstream of the transcription start site and was required for expression in the medial/ventral diencephalon/midbrain in transgenic embryos and for activation in luciferase assay. These findings indicate that Fgf15 is directly regulated by Shh signaling through Gli proteins.

Amino Acid Motifs↗

PubMed1996

Repressor forms of the enhancer-binding protein NrtC: some fail in coupling ATP hydrolysis to open complex formation by sigma 54-holoenzyme.

NtrC (nitrogen regulatory protein C) is a bacterial enhancer-binding protein that activates transcription by catalyzing isomerization of closed complexes between sigma54-holoenzyme and a promoter to open complexes. To catalyze this reaction, NtrC must be phosphorylated and form an appropriate oligomer so that it can hydrolyze ATP. NtrC can also repress transcription by sigma70-holoenzyme. In this paper we characterize "repressor" mutant forms of NtrC from Salmonella typhimurium, forms that have lost the ability to activate transcription by sigma54-holoenzyme (in vitro activity at least 1000-fold lower than wild-type) but retain the ability to repress transcription by sigma70-holoenzyme. The amino acid substitutions in NtrCrepressor proteins that were obtained by classical genetic techniques alter residues in the central domain of the protein, the domain directly responsible for transcriptional activation. Commensurate with this, phosphorylation and the autophosphatase activities of NtrCrepressor proteins, which are functions of the amino-terminal regulatory domain of NtrC, are normal. In addition, these proteins have essentially normal DNA-binding, which is a function of the C-terminal region of NtrC and bind cooperatively to enhancers. (The NtrC(G219K) protein has "improved" DNA-binding, which is discussed.) We previously presented evidence that several NtrCrepressor proteins have impaired ATPase activity. We now show that two other repressor proteins, NtrC(A216V) and NtrC(A220T), have as much ATPase activity as wild-type NtrC when they are phosphorylated and bound to an enhancer and that they have considerably more activity than an unphosphorylated NtrC(constitutive) protein, which is capable of activating transcription. These results demonstrate that NtrC(A216V) and NtrC(A220T) fail in a function of the central domain other than ATPase activity. Although they may fail in contact with sigma54-holoenzyme per se, the fact that alanine is the amino acid normally found at these positions leads us to speculate that these proteins fail in coupling energy to a change in conformation of the polymerase.

Adenosine Triphosphatases↗

PubMed2003

Human endogenous retroviruses with transcriptional potential in the brain.

Genetic studies of neuropsychiatric disorders have often produced conflicting results, which might partly result from the involvement of epigenetic modifications. We intended to explore the possible implication of DNA methylation and human endogenous retroviruses (HERVs) in neuropsychiatric disorders. In the present study, we identified two HERV loci that are expected to retain the transcriptional activity in the brain. One was located on chromosome 1q21-q22 and the other on 22q12. Interestingly, these regions were overlapped with or included in those of schizophrenia-susceptible loci, SCZD9 and SCZD4, respectively. Particularly, the HERV on 22q12 was located in the opposite direction 4 kb downstream of the Synapsin III gene. These HERV loci could afford clear targets for methylation and expression analyses in postmortem brains of patients with psychiatric disorders such as schizophrenia. In addition, we confirmed our previous finding that only a few of particular HERV-K loci were activated among a number of highly homologous loci in teratocarcinoma cell lines. These activated loci included ones common to all teratocarcinoma cell lines analyzed and depending on their male or female origin.

Brain↗

PubMed2002

Protein S1 counteracts the inhibitory effect of the extended Shine-Dalgarno sequence on translation.

There are two major components of Escherichia coli ribosomes directly involved in selection and binding of mRNA during initiation of protein synthesis-the highly conserved 3' end of 16S rRNA (aSD) complementary to the Shine-Dalgarno (SD) domain of mRNA, and the ribosomal protein S1. A contribution of the SD-aSD and S1-mRNA interactions to translation yield in vivo has been evaluated in a genetic system developed to compare efficiencies of various ribosome-binding sites (RBS) in driving beta-galactosidase synthesis from the single-copy (chromosomal) lacZ gene. The in vivo experiments have been supplemented by in vitro toeprinting and gel-mobility shift assays. A shortening of a potential SD-aSD duplex from 10 to 8 and to 6 bp increased the beta-galactosidase yield (four- and sixfold, respectively) suggesting that an extended SD-aSD duplex adversely affects translation, most likely due to its redundant stability causing ribosome stalling at the initiation step. Translation yields were significantly increased upon insertion of the A/U-rich S1 binding targets upstream of the SD region, but the longest SD remained relatively less efficient. In contrast to complete 30S ribosomes, the S1-depleted 30S particles have been able to form an extended SD-aSD duplex, but not the true ternary initiation complex. Taken together, the in vivo and in vitro data allow us to conclude that S1 plays two roles in translation initiation: It forms an essential part of the mRNA-binding track even when mRNA bears a long SD sequence, and through the binding to the 5' untranslated region, it can ensure a substantial enhancing effect on translation.

5' Untranslated Regions↗

PubMed2000

Alleles of the alpha1 immunoglobulin gene 3' enhancer control evolution of IgA nephropathy toward renal failure.

BACKGROUND: IgA nephropathy is the most common glomerular disease. Mechanisms leading to its occurrence and controlling the evolution of the disease remain largely unknown. Various genetic factors have been found, mostly implicating immunologically relevant genes (IgH, TCR, human lymphocyte antigen, and complement loci). A regulatory region recently identified downstream, the alpha1 gene of the IgH locus, was a likely candidate for the control of IgA1 production in patients. Alleles of this region, differing by size, sequence, and orientation of the alpha1 hs1,2 transcriptional enhancer, were first identified through Southern blot hybridization. METHODS: We established a polymerase chain reaction (PCR) method suitable for routine testing that amplifies minisatellites within the alpha1 hs1, 2 enhancer, with variable numbers of tandem repeats (VNTR) defining the two alleles. This assay allowed the typing of 104 patients with IgAN and 83 healthy volunteers. Results from typing of alpha1 hs1,2 alleles were compared with long-term clinical outcome in patients. Enhancer alleles were compared in a luciferase reporter gene assay. RESULTS: The alpha1 hs1,2 alleles do not constitute a predictive factor for IgA nephropathy, since similar allelic frequencies were observed in healthy individuals and in unrelated European patients. In contrast, among patients, homozygosity for the weakest enhancer allele (AA genotype) was significantly correlated with a milder form of the disease, whereas the allele B was associated with severe evolution. The minisatellite region within the alpha1 hs1,2 enhancer carried potential transcription factor-binding sites, and its duplication increased the transcriptional strength of the alpha1 hs1, 2 allele B over that of allele A. CONCLUSION: Altogether, these alleles may constitute a risk factor for the prognosis of IgA nephropathy.

3' Untranslated Regions↗

PubMedDate not supplied

Smokeless tobacco extracts modulate exogenous gene expression in early passage cultured human oral epithelial cells: an in vitro system to study chemical and viral enhancer/promoter interaction.

The increased risk for cancers of the oral cavity from smokeless tobacco use may reflect the interaction of tobacco with genetic factors, such as oncogenes, and other exogenous factors, such as viruses. An in vitro system was developed based on expression of the chloramphenicol acetyltransferase (CAT) reporter gene to study interactions of chemical treatments with viral enhancer/promoters in early passage cell cultures of oral cavity-derived epithelial cells. Expression of CAT in transfected cells was significantly greater with CAT under the control of the cytomegalovirus immediate early enhancer/promoter (pCEP4/CAT) compared to the Rous sarcoma virus long terminal repeat enhancer/promoter (pRSV-cat) and the simian virus 40 (SV40) early promoter (pSV2-cat). No CAT expression was detected using corresponding control plasmids without the CAT reporter gene. Using this system, smokeless tobacco extracts prepared from either dry snuff or moist snuff delayed maximum CAT expression from Day 4 to Day 5, with sustained, significantly increased CAT expression at 12 days compared to the declining CAT expression observed in untreated control cells. Smokeless tobacco extracts can modulate intracellular gene expression. This system provides an in vitro model to test specificity of toxic agents on enhancer/promoter activity and the interaction on exogenous gene expression.

Avian Sarcoma Viruses↗

PubMed1999

SPI-B activates transcription via a unique proline, serine, and threonine domain and exhibits DNA binding affinity differences from PU.1.

SPI-B is a B lymphocyte-specific Ets transcription factor that shares a high degree of similarity with PU.1/SPI-1. In direct contrast to PU.1(-/-) mice that die in utero and lack monocytes, neutrophils, B cells, and T cells, Spi-B-/- mice are viable and exhibit a severe B cell proliferation defect. Since PU.1 is expressed at wild type levels in Spi-B-/- B cells, the mutant mice provide genetic evidence that SPI-B and PU.1 have at least some non-redundant roles in B lymphocytes. To begin to understand the molecular basis for these defects, we delineated functional domains of SPI-B for comparison to those of PU.1. By using a heterologous co-transfection system, we identified two independent transactivation domains in the N terminus of SPI-B. Interestingly, only one of these domains (amino acids 31-61), a proline/serine/threonine-rich region, unique among Ets proteins, is necessary for transactivation of the immunoglobulin lambda light chain enhancer. This transactivation motif is in marked contrast to PU.1, which contains acidic and glutamine-rich domains. In addition, we describe a functional PU.1 site within the c-FES promoter which SPI-B fails to bind efficiently and transactivate. Finally, we show that SPI-B interacts with the PU.1 cofactors Pip, TBP, c-Jun and with lower affinity to nuclear factor interleukin-6beta and retinoblastoma. Taken together, these data suggest that SPI-B binds DNA with a different affinity for certain sites than PU.1 and harbors different transactivation domains. We conclude that SPI-B may activate unique target genes in B lymphocytes and interact with unique, although currently unidentified, cofactors.

Amino Acid Sequence↗

PubMed1992

Brain tumours and lymphomas in transgenic mice that carry HTLV-I LTR/c-myc and Ig/tax genes.

The human T-cell leukemia virus type 1 (HTLV-I) is associated with adult CD4+ T-cell leukemia (ATL) and tropical spastic paraparesis (TSP). In as much as only a small percentage of individuals infected with HTLV-I develop either disease, we set out to model a genetic partner for this virus in an effort to understand and possibly reproduce its pathophysiology. To this end we have developed a binary set of transgenic mice, one bearing the relatively inactive HTLV-I long terminal repeat (LTR) positioned to drive the c-myc oncogene and another bearing a fusion transgene consisting of the immunoglobulin promoter/enhancer driving the gene for the HTLV-I transcription activator, tax. Alone, the tax construct, though expressed in the thymus, spleen, lung and brain, has no deleterious effect. Alone, the HTLV-I LTR/c-myc construct is expressed at very low levels in lymphoid cells and occasionally induces lymphomas in older animals. When these two transgenic lines are mated, bigenic offspring harboring both transgenes exhibit dramatic tumor formation. As in the human, these animals develop CD4+ T-cell lymphomas, but they also develop central nervous system tumors by 25-90 days of age. The syndrome, which is 100% penetrant and lethal, provides an animal model for adult T-cell lymphoma and a source of cultured cells of neurogenic origin.

Animals↗

PubMed2001

Gene therapy of a mouse model of protoporphyria with a self-inactivating erythroid-specific lentiviral vector without preselection.

Successful treatment of blood disorders by gene therapy has several complications, one of which is the frequent lack of selective advantage of genetically corrected cells. Erythropoietic protoporphyria (EPP), caused by a ferrochelatase deficiency, is a good model of hematological genetic disorders with a lack of spontaneous in vivo selection. This disease is characterized by accumulation of protoporphyrin in red blood cells, bone marrow, and other organs, resulting in severe skin photosensitivity. Here we develop a self-inactivating lentiviral vector containing human ferrochelatase cDNA driven by the human ankyrin-1/beta-globin HS-40 chimeric erythroid promoter/enhancer. We collected bone marrow cells from EPP male donor mice for lentiviral transduction and injected them into lethally irradiated female EPP recipient mice. We observed a high transduction efficiency of hematopoietic stem cells resulting in effective gene therapy of primary and secondary recipient EPP mice without any selectable system. Skin photosensitivity was corrected for all secondary engrafted mice and was associated with specific ferrochelatase expression in the erythroid lineage. An erythroid-specific expression was sufficient to reverse most of the clinical and biological manifestations of the disease. This improvement in the efficiency of gene transfer with lentiviruses may contribute to the development of successful clinical protocols for erythropoietic diseases.

Animals↗

PubMed1997

Interleukin-4 protects against a genetically linked lupus-like autoimmune syndrome.

Interleukin-4 (IL-4) provides support for humoral immune responses through upregulation of T helper (Th) type 2 cell differentiation, but it is not known whether IL-4 promotes antibody-mediated autoimmune diseases such as systemic lupus erythematosus (SLE). Here, we show that the constitutive expression of an IL-4 transgene by B cells completely prevents the development of lethal lupus-like glomerulonephritis in the (NZW x C57BL/6.Yaa)F1 murine model of SLE. This was associated with marked changes in the serum levels of IgG subclasses, rather than in the total levels of anti-DNA antibodies, with a lack of IgG3, a decrease of IgG2a, and an increase in IgG1 subclasses, and by a strong reduction in the serum levels of gp70-anti-gp70 immune complexes. This effect of the transgene appears to result from a modulation of the Th1 versus Th2 autoimmune response, since the protected mice displayed comparably modified IgG2a and IgG3 antibody response against exogenous T cell-dependent antigen, but not against T cell-independent antigens. Thus, IL-4 prevents the development of this lupus-like autoimmune disease, most likely by downregulating the appearance of Th1-mediated IgG subclasses of autoantibodies such as the IgG3 autoantibodies which have been shown to be especially nephritogenic.

Animals↗

PubMed2005

Linking structural assembly to gene expression: a novel mechanism for regulating the activity of a sigma54 transcription factor.

In Caulobacter crescentus, the temporal and spatial expression of late flagellar genes is regulated by the sigma54 transcriptional activator, FlbD. Genetic experiments have indicated that the trans-acting factor FliX regulates FlbD in response to the progression of flagellar assembly, repressing FlbD activity until an early flagellar basal body structure is assembled. Following assembly of this structure, FliX is thought to function as an activator of FlbD. Here we have investigated the mechanism of FliX-mediated regulation of FlbD activity. In vitro transcription experiments showed that purified FliX could function as a repressor of FlbD-activated transcription. Transcription activated by a gain-of-function mutant of FlbD (FlbD-1204) that is active in vivo in the absence of an early flagellar structure, was resistant to the repressive effects of FliX. DNA binding studies showed that FliX inhibited the interaction of wild-type FlbD with enhancer DNA but did not effect FlbD-catalysed ATPase activity. DNA binding activity of FlbD-1204 was relatively unaffected by FliX indicating that this mutant protein bypasses the transcriptional requirement for early flagellar assembly by escaping FliX-mediated negative regulation. Gel filtration and co-immunoprecipitation experiments indicated that FliX formed a stable complex with FlbD. These experiments demonstrate that regulation of FlbD activity is unusual among the well-studied sigma54 transcriptional activators, apparently combining a two-component receiver domain with additional control imposed via interaction with a partner protein, FliX.

Adenosine Triphosphatases↗

PubMed1995

Isolation and characterization of a new simian T-cell leukemia virus type 1 from naturally infected celebes macaques (Macaca tonkeana): complete nucleotide sequence and phylogenetic relationship with the Australo-Melanesian human T-cell leukemia virus type 1.

A study of simian T-cell leukemia virus type 1 (STLV-1) infection in a captive colony of 23 Macaca tonkeana macaques indicated that 17 animals had high human T-cell leukemia virus type 1 (HTLV-1) antibody titers. Genealogical analysis suggested mainly a mother-to-offspring transmission of this STLV-1. Three long-term T-cell lines, established from peripheral blood mononuclear cell cultures from three STLV-1-seropositive monkeys, produced HTLV-1 Gag and Env antigens and retroviral particles. The first complete nucleotide sequence of an STLV-1 (9,025 bp), obtained for one of these isolates, indicated an overall genetic organization similar to that of HTLV-1 but with a nucleotide variability for the structural genes ranging from 7.8 to 13.1% compared with the HTLV-1 ATK and STLV-1 PTM3 Asian prototypes. The Tax and Rex regulatory proteins were well conserved, while the pX region, known to encode new proteins in HTLV-1 (open reading frames I and II), was more divergent than that in the ATK strain. Furthermore, a fragment of 522 bp of the gp21 env gene from uncultured peripheral blood mononuclear cell DNAs from five of the STLV-1-infected monkeys was sequenced. Phylogenetic trees constructed with the long terminal repeat and env (gp46 and gp21) regions demonstrated that this new STLV-1 occupies a unique position within the Asian STLV-1 and HTLV-1 isolates, being, by most analyses, related more to the Australo-Melanesian HTLV-1 topotype than to any other Asian STLV-1. These data raise new hypotheses on the possible interspecies viral transmission between monkeys carrying STLV-1 and early Australoid settlers, ancestors of the present day Australo-Melanesian inhabitants, during their migrations from the Southeast Asian land mass to the greater Australian continent.

Amino Acid Sequence↗