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A. Gessain - One of the best experts on this subject based on the ideXlab platform.
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Risk factors for HTLV-1 Infection in Central Africa: A rural population-based survey in Gabon.
PLoS neglected tropical diseases, 2018Co-Authors: Delia Doreen Djuicy, A. Fontanet, Augustin Mouinga-ondémé, Olivier Cassar, Jill-léa Ramassamy, Antony Idam Mamimandjiami, Rodrigue Bikangui, A. GessainAbstract:Background Human T-Lymphotropic Virus type 1 (HTLV-1) is a human oncoretrovirus that infects at least 5 to 10 million people worldwide and is associated with severe diseases. Africa appears as the largest HTLV-1 endemic area. However, the risk factors for the acquisition of HTLV-1 remain poorly understood in Central Africa. Methods We conducted an epidemiological survey between 2013 and 2017, in rural areas of 6 provinces of Gabon, in a rainforest environment. Epidemiological data were obtained and blood samples were collected after informed consent. Plasma were screened for HTLV-1 antibodies by ELISA and the positive samples were then tested by Western blot (WB). Genomic DNA derived from buffy-coat was subjected to two semi-nested PCRs amplifying either HTLV-1 env gene or LTR region fragments. Results We recruited 2,060 individuals over 15 years old, including 1,205 men and 855 women (mean age: 49 years). Of these, 299 were found to be ELISA HTLV-1/2 seropositive. According to WB criteria, 136 were HTLV-1 (6.6%), 25 HTLV-1/2 (1.2%) and 9 HTLV seroreactive (0.4%). PCR results showed that 146 individuals were positive for at least one PCR: 104 for the env gene and 131 for the LTR region. Based on both serological and molecular results, 179 individuals were considered infected with HTLV-1, leading to an overall prevalence of 8.7%. The distribution of HTLV-1 Infection was heterogeneous across the country. Based on multivariable analyses, female gender, increasing age, ethnicity (Pygmy) and multiple hospitalizations (more than 5 times) were found to be independent risk factors for HTLV-1 Infection. Furthermore, a non-human primate bite appeared to be marginally associated with a higher risk of HTLV-1 Infection. Conclusion Based on state-of-the-art serological and molecular methods, we have demonstrated that rural adult populations in Gabon are highly endemic for HTLV-1. Our results regarding risk factors should lead to public health actions aiming to reduce HTLV-1 transmission.
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A Severe Bite From a Nonhuman Primate Is a Major Risk Factor for HTLV-1 Infection in Hunters From Central Africa
Clinical Infectious Diseases, 2015Co-Authors: C. Filippone, E. Betsem, P. Tortevoye, O. Cassar, S. Bassot, A. Froment, A. Fontanet, A. GessainAbstract:HTLV-1 Infection is endemic to Central African populations. The risk factors for HTLV-1 acquisition in humans via the interspecies transmission of STLV-1 (its simian counterpart) remain largely unknown. We studied 269 individuals (254 men, 15 women) bitten by a nonhuman primate (NHP), mostly during hunting activities. These, Pygmies and Bantus, living in the southern Cameroonian rainforest, were matched for sex, age, and ethnicity with individuals from the same settlements reporting no NHP bites. HTLV-1 serology was performed by Western blot on plasma samples. PCR was carried out for HTLV-1 provirus on buffy-coat DNAs. The amplified products were sequenced and analyzed by phylogenetic analyses. HTLV-1 prevalence was 8.6% (23/269) in individuals with bites, vs 1.5% (4/269) in matched controls (P < .001). Moreover, HTLV-1 Infection was linked to bite severity. The 23 HTLV-1-positive bitten individuals reported being bitten by a gorilla (17), chimpanzee (3), or small monkey (3). Thirteen (56%) were coinfected with a simian foamy virus known to be acquired through severe bites. Mother-to-child Infection was excluded in 6 HTLV-1-infected bitten individuals. All the HTLV-1-positive hunters bitten by a gorilla or chimpanzee were infected with a subtype B strain similar to that present in apes from the same area. Two hunters bitten by small monkeys (C. agilis in one case) were infected with a HTLV-1 subtype F strain very similar to the STLV-1 strains present in such monkeys. These results strongly suggest ongoing direct zoonotic acquisition of STLV-1 in humans through severe NHP bites during hunting activities.
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A Severe Bite From a Nonhuman Primate Is a Major Risk Factor for HTLV-1 Infection in Hunters From Central Africa
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2015Co-Authors: C. Filippone, E. Betsem, P. Tortevoye, S. Bassot, A. Froment, A. Fontanet, Olivier Cassar, A. GessainAbstract:Background. HTLV-1 Infection is endemic to Central African populations. The risk factors for HTLV-1 acquisition in humans via the interspecies transmission of STLV-1 (its simian counterpart) remain largely unknown. Methods. We studied 269 individuals (254 men, 15 women) bitten by a nonhuman primate (NHP), mostly during hunting activities. These, Pygmies and Bantus, living in the southern Cameroonian rainforest, were matched for sex, age, and ethnicity with individuals from the same settlements reporting no NHP bites. HTLV-1 serology was performed by Western blot on plasma samples. PCR was carried out for HTLV-1 provirus on buffy-coat DNAs. The amplified products were sequenced and analyzed by phylogenetic analyses. Results. HTLV-1 prevalence was 8.6% (23/269) in individuals with bites, vs 1.5% (4/269) in matched controls (P< .001). Moreover, HTLV-1 Infection was linked to bite severity. The 23 HTLV-1-positive bitten individuals reported being bitten by a gorilla (17), chimpanzee (3), or small monkey (3). Thirteen (56%) were coinfected with a simian foamy virus known to be acquired through severe bites. Mother-to-child Infection was excluded in 6 HTLV1-infected bitten individuals. All the HTLV-1-positive hunters bitten by a gorilla or chimpanzee were infected with a subtype B strain similar to that present in apes from the same area. Two hunters bitten by small monkeys (C. agilis in one case) were infected with a HTLV-1 subtype F strain very similar to the STLV-1 strains present in such monkeys. Conclusions. These results strongly suggest ongoing direct zoonotic acquisition of STLV-1 in humans through severe NHP bites during hunting activities.
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High frequency of HTLV-1 Infection in Bantus and Pygmies from rural Cameroon bitten by non-human primates during hunting
2013Co-Authors: C. Filippone, E. Betsem, P. Tortevoye, S. Bassot, A. Froment, A. Fontanet, A. GessainAbstract:HTLV-1 Infection is endemic in Central Africa, as well as the closely related STLV-1 found in several non-human primates (NHPs). Like other retroviruses, acquisition through interspecies transmission is strongly suggested but needs to be investigated. We analyzed 269 selected individuals (254 men, 15 women, average age 43.5 years) for whom a direct contact (mainly a severe bite) with a NHP occurred. This happened mostly during hunting activities and involved bleeding and body fluids exchange with at least saliva/blood contact. The same number of persons who live in the same villages/settlements but did not report any bite by NHPs was matched according to sex, age and ethnicity. Both groups include either Pygmies or Bantus living in the rain forest of South Cameroon. Plasma were tested for HTLV serology by WB, and proviral DNA was searched in buffy-coat DNA by 3 HTLV generic and one HTLV-1 specific PCR. HTLV-1 prevalence was of 8.5% (23/269) among bitten individuals versus 1.5% (4/269) observed in the controls (p
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A major susceptibility locus for HTLV-1 Infection in childhood maps to chromosome 6q27
Human molecular genetics, 2006Co-Authors: Sabine Plancoulaine, P. Tortevoye, A. Gessain, Anne Boland-auge, Alexandre Vasilescu, Fumihiko Matsuda, Laurent AbelAbstract:Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is a human oncoretrovirus causing adult T-cell leukemia/lymphoma and chronic neuromyelopathy. We previously showed by segregation analysis that a dominant gene controls HTLV-1 Infection through breast-feeding in children of African origin. Here, we report the mapping of this locus by a genome-wide linkage analysis based on the genetic model provided by segregation analysis. Five pedigrees of African origin with HTLV-1 seropositive children were included in the study. Significant evidence for linkage (LOD score of 3.36, P 5 0.00004) was obtained for chomosomal region 6q27 when using the robust analysis including only HTLV-1-infected subjects. When HTLV-1 seronegative children born to infected mothers were added in the analysis, a maximum LOD score of 2.79 (P 5 0.0002) was obtained for chomosome 2p25. This result was mostly due to the largest pedigree of our sample, which alone gave a LOD score of 2.90 (P 5 0.00013). We further excluded the role of exonic variants of two candidate genes located in the linked regions, CCR6 (chemokine receptor 6) in 6q27 and ID2 (inhibitor of DNA binding 2) in 2p25. Our results, mapping a major susceptibility locus to chromosome 6q27 and suggesting genetic heterogeneity with another locus at 2p25, pave the way to the determination of the molecular basis of predisposition to HTLV-1 Infection in children.
Charles R. M. Bangham - One of the best experts on this subject based on the ideXlab platform.
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Reducing the global burden of HTLV-1 Infection: an agenda for research and action
Antiviral research, 2016Co-Authors: Luc Willems, Charles R. M. Bangham, Hideki Hasegawa, Roberto S. Accolla, Ali Bazarbachi, Umberto Bertazzoni, Anna Bárbara F. Carneiro-proietti, Hua Cheng, Luigi Chieco-bianchi, Vincenzo CiminaleAbstract:Even though an estimated 10-20 million people worldwide are infected with the oncogenic retrovirus, human T-lymphotropic virus type 1 (HTLV-1), its epidemiology is poorly understood, and little effort has been made to reduce its prevalence. In response to this situation, the Global Virus Network launched a taskforce in 2014 to develop new methods of prevention and treatment of HTLV-1 Infection and promote basic research. HTLV-1 is the etiological agent of two life-threatening diseases, adult T-cell leukemia and HTLV-associated myelopathy/tropical spastic paraparesis, for which no effective therapy is currently available. Although the modes of transmission of HTLV-1 resemble those of the more familiar HIV-1, routine diagnostic methods are generally unavailable to support the prevention of new Infections. In the present article, the Taskforce proposes a series of actions to expand epidemiological studies; increase research on mechanisms of HTLV-1 persistence, replication and pathogenesis; discover effective treatments; and develop prophylactic and therapeutic vaccines.
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Frequency and function of KIR CD8 T cells in HTLV-1 Infection.
Retrovirology, 2014Co-Authors: Katie Twigger, Becca Asquith, Graham P. Taylor, Aileen G. Rowan, Nafisa-katrin Seich Al Basatena, Aidan Macnamara, Christelle Retière, Keith G. Gould, Charles R. M. BanghamAbstract:An efficient antiviral cytotoxic T lymphocyte (CTL) response to HTLV-1 Infection maintains a low proviral load (PVL), reducing the risk of HAM/TSP. Host genotype, particularly of HLA class I, is a major determinant of CTL efficiency, and the influence of specific HLA class I alleles on HTLV-1 immunity is well documented. We recently showed that killer immunoglobulin-like receptor (KIR) genotype also influences CTL efficiency, by affecting HLA class I-mediated HTLV-1 immunity. Possession of the KIR2DL2 gene enhanced the effect of known protective or detrimental HLA class I alleles on PVL and HAM/TSP risk. This study aims to profile the frequency and function of CD8+ T cells expressing KIR2DL2 and other KIRs in HTLV-1 Infection. Analysing total KIR expression showed the presence of KIR+CD8+ T cells, NK cells and CD4+ T cells in PBMCs from uninfected and HTLV-1+ donors. A subset of HTLV-1+ donors had high frequencies of total KIR+CD8+ T cells. Analysing individual KIRs revealed the presence of KIR2DL2+CD8+ T cells in HTLV-1+ donors. Preliminary data from PBMCs stimulated with Tax peptides indicates that KIR2DL2+CD8+ T cells constitute a very small proportion of the IFNγ-producing Tax-specific CD8+ T cell population. HTLV-1+ asymptomatic carriers had higher frequencies of IFNγ-producing Tax-specific KIR2DL2+CD8+ T cells than donors with HAM/TSP did. Further work is underway to characterise the function of Tax-specific CD8+ T cells by staining with anti-CD107a, anti-IFNγ and the HLA-A2/Tax11-19 pentamer, and to compare the frequency and function of KIR2DL2+CD8+ T cells with those expressing other 2-domain KIRs.
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Estimation of clonal diversity in HTLV-1 Infection
Retrovirology, 2014Co-Authors: Daniel J. Laydon, Anat Melamed, Aaron Sim, Nicolas Gillet, Kathleen Sim, Sam Darko, J. Simon Kroll, Daniel C. Douek, David Price, Charles R. M. BanghamAbstract:Within hosts, Human T-Lymphotropic Virus Type-1 (HTLV-1) is spread through de novo Infection and infected cell proliferation, producing multiple T cell clones (infected cells with the same genomic proviral integration site). Between hosts, the number of clones observed from a 10μg sample of DNA varies by up to three orders of magnitude. The question arises: what is the total number of clones in the host from which that sample was drawn? Considering each clone as a “species”, the question becomes analogous to the “unseen species problem” in population ecology. We tested four species richness (number of species) estimators, and a novel approach, “DivE”, using three independent datasets: (i) viral populations from patients infected with HTLV-1, (ii) T cell antigen receptor clonotype repertoires, and (iii) microbial data from infant faecal samples. In all datasets, DivE was substantially more accurate than the ecological estimators, which were strongly biased by sample size when applied to datasets where the majority of species was not already present. DivE can also be used to estimate with accuracy the population clone structure from small samples. Previous estimates of HTLV-1 clone diversity in vivo were in the order of 102, and have increased in line with method sensitivity. In contrast, the mean estimated number of clones in the circulation of a single host (asymptomatic carriers and patients with chronic inflammation) by DivE was more than two logs higher than previously estimated. These estimates will inform our understanding of the dynamics and pathogenesis of HTLV-1 Infection.
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HTLV-1 clonality in adult T-cell leukaemia and non-malignant HTLV-1 Infection.
Seminars in cancer biology, 2013Co-Authors: Charles R. M. Bangham, Lucy Cook, Anat MelamedAbstract:Human T lymphotropic virus type 1 (HTLV-1) causes a range of chronic inflammatory diseases and an aggressive malignancy of T lymphocytes known as adult T-cell leukaemia/lymphoma (ATLL). A cardinal feature of HTLV-1 Infection is the presence of expanded clones of HTLV-1-infected T cells, which may persist for decades. A high viral burden (proviral load) is associated with both the inflammatory and malignant diseases caused by HTLV-1, and it has been believed that the oligoclonal expansion of infected cells predisposes to these diseases. However, it is not understood what regulates the clonality of HTLV-1 in vivo, that is, the number and abundance of HTLV-1-infected T cell clones. We review recent advances in the understanding of HTLV-1 Infection and disease that have come from high-throughput quantification and analysis of HTLV-1 clonality in natural Infection.
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Genome-wide Determinants of Proviral Targeting, Clonal Abundance and Expression in Natural HTLV-1 Infection
PLoS pathogens, 2013Co-Authors: Anat Melamed, Graham P. Taylor, Yuetsu Tanaka, Daniel J. Laydon, Nicolas Gillet, Charles R. M. BanghamAbstract:The regulation of proviral latency is a central problem in retrovirology. We postulate that the genomic integration site of human T lymphotropic virus type 1 (HTLV-1) determines the pattern of expression of the provirus, which in turn determines the abundance and pathogenic potential of infected T cell clones in vivo. We recently developed a high-throughput method for the genome-wide amplification, identification and quantification of proviral integration sites. Here, we used this protocol to test two hypotheses. First, that binding sites for transcription factors and chromatin remodelling factors in the genome flanking the proviral integration site of HTLV-1 are associated with integration targeting, spontaneous proviral expression, and in vivo clonal abundance. Second, that the transcriptional orientation of the HTLV-1 provirus relative to that of the nearest host gene determines spontaneous proviral expression and in vivo clonal abundance. Integration targeting was strongly associated with the presence of a binding site for specific host transcription factors, especially STAT1 and p53. The presence of the chromatin remodelling factors BRG1 and INI1 and certain host transcription factors either upstream or downstream of the provirus was associated respectively with silencing or spontaneous expression of the provirus. Cells expressing HTLV-1 Tax protein were significantly more frequent in clones of low abundance in vivo. We conclude that transcriptional interference and chromatin remodelling are critical determinants of proviral latency in natural HTLV-1 Infection.
Michael Dale Lairmore - One of the best experts on this subject based on the ideXlab platform.
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Abstract 405: HTLV-1 Infection of humanized SCID mice recapitulates adult T-cell leukemia/lymphoma (ATLL) development
Tumor Biology, 2010Co-Authors: Prabal Banerjee, Michael Dale Lairmore, Lindsey B. Crawford, Gerold Feuer, Mark A. BeilkeAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Human T-lymphotropic virus type-1 (HTLV-1) is the etiologic agent of Adult T-cell leukemia/lymphoma (ATLL), an aggressive CD4+/CD25+ T cell malignancy. The early molecular events induced by HTLV-1 Infection as well as the role of various viral genes in the induction of leukemia remain unclear, predominantly due to the lack of an animal model that recapitulates ATLL development. We have previously demonstrated that HTLV-1 is capable of infecting human hematopoietic progenitor and stem cells (CD34+ HP/HSCs) and that Infection of CD34+ HPCs has dramatically different biological effects in comparison to Infection of mature T lymphocytes. To determine if HTLV-1 Infection of CD34+ HP/HSCs recapitulates leukemogenesis in vivo, human hematopoiesis was reconstituted in NOD/SCID mice by injection of human CD34+ HPCs infected ex vivo with HTLV-1. Humanized NOD/SCID (HU-SCID) mice infected with HTLV-1 (HTLV-1-HU-SCID) consistently developed CD4+CD25+ T cell lymphomas with clinical characteristics associated with ATLL at ∼10 weeks post-reconstitution and show significantly elevated levels of HTLV-1 infected human CD4+ T cells in the thymus, mesenteric lymph node, spleen and peripheral blood. Lymphoma cells successfully engrafted in naive NOD/SCID mice when injected into the peritoneal cavity and maintain the expression of viral proteins, gp46env and p19gag. Moreover these infected mice showed hyperproliferation of infected human stem cells (CD34+CD38−) in the bone marrow suggesting that HP/HSCs represents viral reservoir target cells which maintain HTLV-1 Infection for extended periods of time in vivo. We speculate that HTLV-1 Infection of hematopoietic stem cells establishes a virally-infected “cancer stem cell” which subsequently gives rise ATL in patients. Notably, CD34+ HPCs isolated from HTLV-1 infected patient PBL demonstrate proviral integrations, suggesting that these cells harbor Infection in humans. CD34+ HPCs transduced with a lentivirus vector expressing the HTLV-1 Tax gene (Tax1) also results in CD4+/CD25+ T cell leukemia/lymphoma in HU-SCID mice, suggesting that Tax1 expression is sufficient for lymphomagenesis. HTLV-1 Infection of humanized NOD/SCID mice represents a novel in vivo model which recapitulates viral lymphomagenesis and provides a compelling system to investigate and characterize molecular events in human stem cells in the initiation and progression to ATLL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 405.
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Cyclosporine-induced immune suppression alters establishment of HTLV-1 Infection in a rabbit model.
Blood, 2009Co-Authors: Rashade A H Haynes, Evan Ware, Christopher Premanandan, Bevin Zimmerman, Andrew J. Phipps, Michael Dale LairmoreAbstract:Human T-lymphotropic virus type 1 (HTLV-1) Infection causes adult T-cell leukemia and several lymphocyte-mediated inflammatory diseases. Persistent HTLV-1 Infection is determined by a balance between host immune responses and virus spread. Immunomodulatory therapy involving HTLV-1–infected patients occurs in a variety of clinical settings. Knowledge of how these treatments influence host-virus relationships is not understood. In this study, we examined the effects of cyclosporine A (CsA)–induced immune suppression during early Infection of HTLV-1. Twenty-four New Zealand white rabbits were split into 4 groups. Three groups were treated with either 10 or 20 mg/kg CsA or saline before Infection. The fourth group was treated with 20 mg/kg CsA 1 week after Infection. Immune suppression, plasma CsA concentration, ex vivo lymphocyte HTLV-1 p19 production, anti–HTLV-1 serologic responses, and proviral load levels were measured during Infection. Our data indicated that CsA treatment before HTLV-1 Infection enhanced early viral expression compared with untreated HTLV-1–infected rabbits, and altered long-term viral expression parameters. However, CsA treatment 1 week after Infection diminished HTLV-1 expression throughout the 10-week study course. Collectively, these data indicate immunologic control is a key determinant of early HTLV-1 spread and have important implications for therapeutic intervention during HTLV-1–associated diseases.
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HTLV-1 Infection of Humanized SCID mice recapitulates Adult T-cell Leukemia/Lymphoma (ATLL) development.
Retrovirology, 2009Co-Authors: Prabal Banerjee, Michael Dale Lairmore, Michelle Sieburg, Lindsey B. Crawford, Adam Tripp, William J. Harrington, Mark A. Beilke, Gerold FeuerAbstract:Human T-lymphotropic virus type-1 (HTLV-1) is the etiologic agent of Adult T-cell leukemia/lymphoma (ATLL), an aggressive CD4+/CD25+T cell malignancy. The early molecular events induced by HTLV-1 Infection as well as the role of various viral genes in the induction of leukemia remain unclear, predominantly due to the lack of an animal model that recapitulates ATLL development. We have previously demonstrated that HTLV-1 is capable of infecting human hematopoietic progenitor and stem cells (CD34+HP/HSCs) and that Infection of CD34+HPCs has dramatically different biological effects in comparison to Infection of mature T lymphocytes. To determine if HTLV-1 Infection of CD34+HP/HSCs recapitulates leukemogenesis in vivo, human hematopoiesis was reconstituted in NOD/SCID mice by injection of human CD34+HPCs infected ex vivo with HTLV-1. Humanized NOD/SCID (HU-SCID) mice infected with HTLV-1 (HTLV-1-HU-SCID) consistently developed CD4+CD25+T cell lymphomas with clinical characteristics associated with ATLL at ~10 weeks post-reconstitution and show significantly elevated levels of HTLV-1 infected human CD4+T cells in the thymus, mesenteric lymph node, spleen and peripheral blood. Lymphoma cells successfully engrafted in naive NOD/SCID mice when injected into the peritoneal cavity and maintain the expression of viral proteins, gp46env and p19gag. Moreover these infected mice showed hyperproliferation of infected human stem cells (CD34+CD38-) in the bone marrow suggesting that HP/HSCs represents viral reservoir target cells which maintain HTLV-1 Infection for extended periods of time in vivo. We speculate that HTLV-1 Infection of hematopoietic stem cells establishes a virally-infected ''cancer stem cell'' which subsequently gives rise ATL in patients. Notably, CD34+HPCs isolated from HTLV-1 infected patient PBL demonstrate proviral integrations, suggesting that these cells harbor Infection in humans. CD34+HPCs transduced with a lentivirus vector expressing the HTLV-1 Tax gene (Tax1) also results in CD4+/CD25+T cell leukemia/lymphoma in HU-SCID mice, suggesting that Tax1 expression is sufficient for lymphomagenesis. HTLV-1 Infection of humanized NOD/SCID mice represents a novel in vivo model which recapitulates viral lymphomagenesis and provides a compelling system to investigate and characterize molecular events in human stem cells in the initiation and progression to ATLL.
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HTLV-1 Infection of Human Hematopoietic Stem Cells Induces a Novel T Cell Lymphoma in Humanized SCID Mice
Blood, 2008Co-Authors: Prabal Banerjee, Michael Dale Lairmore, Michelle Sieburg, Lindsey B. Crawford, William J. Harrington, Mark A. Beilke, Patrick L. Green, Gerold FeuerAbstract:Human T-lymphotropic virus type-1 (HTLV-1) is a human retrovirus linked to cancer and is the etiologic agent of Adult T-cell leukemia/lymphoma (ATLL), an aggressive CD4 + /CD25 + T cell malignancy. The early molecular events induced by HTLV-1 Infection as well as the role of various viral genes in the induction of leukemia remain unclear, predominantly due to the lack of an animal model that recapitulates ATLL development. HTLV-1 Infection of humanized NOD/SCID mice (HTLV-1- HU-SCID) was achieved by inoculation of NOD/SCID mice with CD34 + hematopoietic progenitor cells and stem cells (CD34 + HP/HSCs) infected ex vivo with HTLV-1. HTLV-1-HU-NOD/SCIDmice consistently developed CD4 + CD25 + T cell lymphomas with clinical characteristics associated with ATLL and infected mice showed hyperproliferation of infected human stem cells (CD34 + CD38 − ) in the bone marrow. Inoculation of NOD/SCID mice withCD34 + HP/HSCs transduced with a lentivirus vector (LV) expressing the HTLV-1oncoprotein (Tax1) also developed CD4 + CD25 + lymphomas. The HTLV-1 bZIP protein(HBZ), encoded by the minus strand of the HTLV-1 genome, is expressed in all ATLL cells and has been implicated in the maintenance of leukemogenesis. HBZ has previously been previously shown to interact with numerous cellular factors and can modulate Tax1 activity in vitro . To establish the role of HBZ in HTLV-1 replication and leukemogenesis in vivo , HU-SCID mice were infected with an infectious proviral clone lacking functional HBZ (HTLV-1ΔHBZ). HTLV-1ΔHBZ-infected HU-SCID mice developed lymphoproliferations with an immature preleukemic CD4 − CD8 − CD90 + phenotype starting at ~10 weeks post-reconstitution. In contrast wild type HTLV-1 Infection reproducibly induces a mature CD4 + CD25 + CD90 − lymphoma. Lymphoma cells successfully engrafted naive NOD/SCID mice when injected into the peritoneal cavity and these cells maintain the expression of viral proteins, gp46 env and p19 gag . HTLV-1 Infection of CD34 + HP/HSCs and the recapitulation of a lymphoma similar to ATLL in HU-NOD/SCID mice suggest that hematopoietic stem cells provide a relevant cellular target and viral reservoir in vivo and that Infection of these cells contribute to viral lymphomagenesis in humans. The HTLV-1-HU-SCID mouse model presents a compelling in vivo model to characterize molecular initiation and progression of events in the generation of ATL and to establish the role of HTLV-1 auxiliary proteins in viral pathogenesis.
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Animal models for human T-lymphotropic virus type 1 (HTLV-1) Infection and transformation
Oncogene, 2005Co-Authors: Michael Dale Lairmore, Lee Silverman, Lee RatnerAbstract:Over the past 25 years, animal models of human T-lymphotropic virus type 1 (HTLV-1) Infection and transformation have provided critical knowledge about viral and host factors in adult T-cell leukemia/lymphoma (ATL). The virus consistently infects rabbits, some non-human primates, and to a lesser extent rats. In addition to providing fundamental concepts in viral transmission and immune responses against HTLV-1 Infection, these models have provided new information about the role of viral proteins in carcinogenesis. Mice and rats, in particular immunodeficient strains, are useful models to assess immunologic parameters mediating tumor outgrowth and therapeutic invention strategies against lymphoma. Genetically altered mice including both transgenic and knockout mice offer important models to test the role of specific viral and host genes in the development of HTLV-1-associated lymphoma. Novel approaches in genetic manipulation of both HTLV-1 and animal models are available to address the complex questions that remain about viral-mediated mechanisms of cell transformation and disease. Current progress in the understanding of the molecular events of HTLV-1 Infection and transformation suggests that answers to these questions are approachable using animal models of HTLV-1-associated lymphoma
Gerold Feuer - One of the best experts on this subject based on the ideXlab platform.
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Abstract 405: HTLV-1 Infection of humanized SCID mice recapitulates adult T-cell leukemia/lymphoma (ATLL) development
Tumor Biology, 2010Co-Authors: Prabal Banerjee, Michael Dale Lairmore, Lindsey B. Crawford, Gerold Feuer, Mark A. BeilkeAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Human T-lymphotropic virus type-1 (HTLV-1) is the etiologic agent of Adult T-cell leukemia/lymphoma (ATLL), an aggressive CD4+/CD25+ T cell malignancy. The early molecular events induced by HTLV-1 Infection as well as the role of various viral genes in the induction of leukemia remain unclear, predominantly due to the lack of an animal model that recapitulates ATLL development. We have previously demonstrated that HTLV-1 is capable of infecting human hematopoietic progenitor and stem cells (CD34+ HP/HSCs) and that Infection of CD34+ HPCs has dramatically different biological effects in comparison to Infection of mature T lymphocytes. To determine if HTLV-1 Infection of CD34+ HP/HSCs recapitulates leukemogenesis in vivo, human hematopoiesis was reconstituted in NOD/SCID mice by injection of human CD34+ HPCs infected ex vivo with HTLV-1. Humanized NOD/SCID (HU-SCID) mice infected with HTLV-1 (HTLV-1-HU-SCID) consistently developed CD4+CD25+ T cell lymphomas with clinical characteristics associated with ATLL at ∼10 weeks post-reconstitution and show significantly elevated levels of HTLV-1 infected human CD4+ T cells in the thymus, mesenteric lymph node, spleen and peripheral blood. Lymphoma cells successfully engrafted in naive NOD/SCID mice when injected into the peritoneal cavity and maintain the expression of viral proteins, gp46env and p19gag. Moreover these infected mice showed hyperproliferation of infected human stem cells (CD34+CD38−) in the bone marrow suggesting that HP/HSCs represents viral reservoir target cells which maintain HTLV-1 Infection for extended periods of time in vivo. We speculate that HTLV-1 Infection of hematopoietic stem cells establishes a virally-infected “cancer stem cell” which subsequently gives rise ATL in patients. Notably, CD34+ HPCs isolated from HTLV-1 infected patient PBL demonstrate proviral integrations, suggesting that these cells harbor Infection in humans. CD34+ HPCs transduced with a lentivirus vector expressing the HTLV-1 Tax gene (Tax1) also results in CD4+/CD25+ T cell leukemia/lymphoma in HU-SCID mice, suggesting that Tax1 expression is sufficient for lymphomagenesis. HTLV-1 Infection of humanized NOD/SCID mice represents a novel in vivo model which recapitulates viral lymphomagenesis and provides a compelling system to investigate and characterize molecular events in human stem cells in the initiation and progression to ATLL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 405.
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HTLV-1 Infection of Humanized SCID mice recapitulates Adult T-cell Leukemia/Lymphoma (ATLL) development.
Retrovirology, 2009Co-Authors: Prabal Banerjee, Michael Dale Lairmore, Michelle Sieburg, Lindsey B. Crawford, Adam Tripp, William J. Harrington, Mark A. Beilke, Gerold FeuerAbstract:Human T-lymphotropic virus type-1 (HTLV-1) is the etiologic agent of Adult T-cell leukemia/lymphoma (ATLL), an aggressive CD4+/CD25+T cell malignancy. The early molecular events induced by HTLV-1 Infection as well as the role of various viral genes in the induction of leukemia remain unclear, predominantly due to the lack of an animal model that recapitulates ATLL development. We have previously demonstrated that HTLV-1 is capable of infecting human hematopoietic progenitor and stem cells (CD34+HP/HSCs) and that Infection of CD34+HPCs has dramatically different biological effects in comparison to Infection of mature T lymphocytes. To determine if HTLV-1 Infection of CD34+HP/HSCs recapitulates leukemogenesis in vivo, human hematopoiesis was reconstituted in NOD/SCID mice by injection of human CD34+HPCs infected ex vivo with HTLV-1. Humanized NOD/SCID (HU-SCID) mice infected with HTLV-1 (HTLV-1-HU-SCID) consistently developed CD4+CD25+T cell lymphomas with clinical characteristics associated with ATLL at ~10 weeks post-reconstitution and show significantly elevated levels of HTLV-1 infected human CD4+T cells in the thymus, mesenteric lymph node, spleen and peripheral blood. Lymphoma cells successfully engrafted in naive NOD/SCID mice when injected into the peritoneal cavity and maintain the expression of viral proteins, gp46env and p19gag. Moreover these infected mice showed hyperproliferation of infected human stem cells (CD34+CD38-) in the bone marrow suggesting that HP/HSCs represents viral reservoir target cells which maintain HTLV-1 Infection for extended periods of time in vivo. We speculate that HTLV-1 Infection of hematopoietic stem cells establishes a virally-infected ''cancer stem cell'' which subsequently gives rise ATL in patients. Notably, CD34+HPCs isolated from HTLV-1 infected patient PBL demonstrate proviral integrations, suggesting that these cells harbor Infection in humans. CD34+HPCs transduced with a lentivirus vector expressing the HTLV-1 Tax gene (Tax1) also results in CD4+/CD25+T cell leukemia/lymphoma in HU-SCID mice, suggesting that Tax1 expression is sufficient for lymphomagenesis. HTLV-1 Infection of humanized NOD/SCID mice represents a novel in vivo model which recapitulates viral lymphomagenesis and provides a compelling system to investigate and characterize molecular events in human stem cells in the initiation and progression to ATLL.
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HTLV-1 Infection of Human Hematopoietic Stem Cells Induces a Novel T Cell Lymphoma in Humanized SCID Mice
Blood, 2008Co-Authors: Prabal Banerjee, Michael Dale Lairmore, Michelle Sieburg, Lindsey B. Crawford, William J. Harrington, Mark A. Beilke, Patrick L. Green, Gerold FeuerAbstract:Human T-lymphotropic virus type-1 (HTLV-1) is a human retrovirus linked to cancer and is the etiologic agent of Adult T-cell leukemia/lymphoma (ATLL), an aggressive CD4 + /CD25 + T cell malignancy. The early molecular events induced by HTLV-1 Infection as well as the role of various viral genes in the induction of leukemia remain unclear, predominantly due to the lack of an animal model that recapitulates ATLL development. HTLV-1 Infection of humanized NOD/SCID mice (HTLV-1- HU-SCID) was achieved by inoculation of NOD/SCID mice with CD34 + hematopoietic progenitor cells and stem cells (CD34 + HP/HSCs) infected ex vivo with HTLV-1. HTLV-1-HU-NOD/SCIDmice consistently developed CD4 + CD25 + T cell lymphomas with clinical characteristics associated with ATLL and infected mice showed hyperproliferation of infected human stem cells (CD34 + CD38 − ) in the bone marrow. Inoculation of NOD/SCID mice withCD34 + HP/HSCs transduced with a lentivirus vector (LV) expressing the HTLV-1oncoprotein (Tax1) also developed CD4 + CD25 + lymphomas. The HTLV-1 bZIP protein(HBZ), encoded by the minus strand of the HTLV-1 genome, is expressed in all ATLL cells and has been implicated in the maintenance of leukemogenesis. HBZ has previously been previously shown to interact with numerous cellular factors and can modulate Tax1 activity in vitro . To establish the role of HBZ in HTLV-1 replication and leukemogenesis in vivo , HU-SCID mice were infected with an infectious proviral clone lacking functional HBZ (HTLV-1ΔHBZ). HTLV-1ΔHBZ-infected HU-SCID mice developed lymphoproliferations with an immature preleukemic CD4 − CD8 − CD90 + phenotype starting at ~10 weeks post-reconstitution. In contrast wild type HTLV-1 Infection reproducibly induces a mature CD4 + CD25 + CD90 − lymphoma. Lymphoma cells successfully engrafted naive NOD/SCID mice when injected into the peritoneal cavity and these cells maintain the expression of viral proteins, gp46 env and p19 gag . HTLV-1 Infection of CD34 + HP/HSCs and the recapitulation of a lymphoma similar to ATLL in HU-NOD/SCID mice suggest that hematopoietic stem cells provide a relevant cellular target and viral reservoir in vivo and that Infection of these cells contribute to viral lymphomagenesis in humans. The HTLV-1-HU-SCID mouse model presents a compelling in vivo model to characterize molecular initiation and progression of events in the generation of ATL and to establish the role of HTLV-1 auxiliary proteins in viral pathogenesis.
Mark A. Beilke - One of the best experts on this subject based on the ideXlab platform.
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Abstract 405: HTLV-1 Infection of humanized SCID mice recapitulates adult T-cell leukemia/lymphoma (ATLL) development
Tumor Biology, 2010Co-Authors: Prabal Banerjee, Michael Dale Lairmore, Lindsey B. Crawford, Gerold Feuer, Mark A. BeilkeAbstract:Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Human T-lymphotropic virus type-1 (HTLV-1) is the etiologic agent of Adult T-cell leukemia/lymphoma (ATLL), an aggressive CD4+/CD25+ T cell malignancy. The early molecular events induced by HTLV-1 Infection as well as the role of various viral genes in the induction of leukemia remain unclear, predominantly due to the lack of an animal model that recapitulates ATLL development. We have previously demonstrated that HTLV-1 is capable of infecting human hematopoietic progenitor and stem cells (CD34+ HP/HSCs) and that Infection of CD34+ HPCs has dramatically different biological effects in comparison to Infection of mature T lymphocytes. To determine if HTLV-1 Infection of CD34+ HP/HSCs recapitulates leukemogenesis in vivo, human hematopoiesis was reconstituted in NOD/SCID mice by injection of human CD34+ HPCs infected ex vivo with HTLV-1. Humanized NOD/SCID (HU-SCID) mice infected with HTLV-1 (HTLV-1-HU-SCID) consistently developed CD4+CD25+ T cell lymphomas with clinical characteristics associated with ATLL at ∼10 weeks post-reconstitution and show significantly elevated levels of HTLV-1 infected human CD4+ T cells in the thymus, mesenteric lymph node, spleen and peripheral blood. Lymphoma cells successfully engrafted in naive NOD/SCID mice when injected into the peritoneal cavity and maintain the expression of viral proteins, gp46env and p19gag. Moreover these infected mice showed hyperproliferation of infected human stem cells (CD34+CD38−) in the bone marrow suggesting that HP/HSCs represents viral reservoir target cells which maintain HTLV-1 Infection for extended periods of time in vivo. We speculate that HTLV-1 Infection of hematopoietic stem cells establishes a virally-infected “cancer stem cell” which subsequently gives rise ATL in patients. Notably, CD34+ HPCs isolated from HTLV-1 infected patient PBL demonstrate proviral integrations, suggesting that these cells harbor Infection in humans. CD34+ HPCs transduced with a lentivirus vector expressing the HTLV-1 Tax gene (Tax1) also results in CD4+/CD25+ T cell leukemia/lymphoma in HU-SCID mice, suggesting that Tax1 expression is sufficient for lymphomagenesis. HTLV-1 Infection of humanized NOD/SCID mice represents a novel in vivo model which recapitulates viral lymphomagenesis and provides a compelling system to investigate and characterize molecular events in human stem cells in the initiation and progression to ATLL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 405.
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HTLV-1 Infection of Humanized SCID mice recapitulates Adult T-cell Leukemia/Lymphoma (ATLL) development.
Retrovirology, 2009Co-Authors: Prabal Banerjee, Michael Dale Lairmore, Michelle Sieburg, Lindsey B. Crawford, Adam Tripp, William J. Harrington, Mark A. Beilke, Gerold FeuerAbstract:Human T-lymphotropic virus type-1 (HTLV-1) is the etiologic agent of Adult T-cell leukemia/lymphoma (ATLL), an aggressive CD4+/CD25+T cell malignancy. The early molecular events induced by HTLV-1 Infection as well as the role of various viral genes in the induction of leukemia remain unclear, predominantly due to the lack of an animal model that recapitulates ATLL development. We have previously demonstrated that HTLV-1 is capable of infecting human hematopoietic progenitor and stem cells (CD34+HP/HSCs) and that Infection of CD34+HPCs has dramatically different biological effects in comparison to Infection of mature T lymphocytes. To determine if HTLV-1 Infection of CD34+HP/HSCs recapitulates leukemogenesis in vivo, human hematopoiesis was reconstituted in NOD/SCID mice by injection of human CD34+HPCs infected ex vivo with HTLV-1. Humanized NOD/SCID (HU-SCID) mice infected with HTLV-1 (HTLV-1-HU-SCID) consistently developed CD4+CD25+T cell lymphomas with clinical characteristics associated with ATLL at ~10 weeks post-reconstitution and show significantly elevated levels of HTLV-1 infected human CD4+T cells in the thymus, mesenteric lymph node, spleen and peripheral blood. Lymphoma cells successfully engrafted in naive NOD/SCID mice when injected into the peritoneal cavity and maintain the expression of viral proteins, gp46env and p19gag. Moreover these infected mice showed hyperproliferation of infected human stem cells (CD34+CD38-) in the bone marrow suggesting that HP/HSCs represents viral reservoir target cells which maintain HTLV-1 Infection for extended periods of time in vivo. We speculate that HTLV-1 Infection of hematopoietic stem cells establishes a virally-infected ''cancer stem cell'' which subsequently gives rise ATL in patients. Notably, CD34+HPCs isolated from HTLV-1 infected patient PBL demonstrate proviral integrations, suggesting that these cells harbor Infection in humans. CD34+HPCs transduced with a lentivirus vector expressing the HTLV-1 Tax gene (Tax1) also results in CD4+/CD25+T cell leukemia/lymphoma in HU-SCID mice, suggesting that Tax1 expression is sufficient for lymphomagenesis. HTLV-1 Infection of humanized NOD/SCID mice represents a novel in vivo model which recapitulates viral lymphomagenesis and provides a compelling system to investigate and characterize molecular events in human stem cells in the initiation and progression to ATLL.
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HTLV-1 Infection of Human Hematopoietic Stem Cells Induces a Novel T Cell Lymphoma in Humanized SCID Mice
Blood, 2008Co-Authors: Prabal Banerjee, Michael Dale Lairmore, Michelle Sieburg, Lindsey B. Crawford, William J. Harrington, Mark A. Beilke, Patrick L. Green, Gerold FeuerAbstract:Human T-lymphotropic virus type-1 (HTLV-1) is a human retrovirus linked to cancer and is the etiologic agent of Adult T-cell leukemia/lymphoma (ATLL), an aggressive CD4 + /CD25 + T cell malignancy. The early molecular events induced by HTLV-1 Infection as well as the role of various viral genes in the induction of leukemia remain unclear, predominantly due to the lack of an animal model that recapitulates ATLL development. HTLV-1 Infection of humanized NOD/SCID mice (HTLV-1- HU-SCID) was achieved by inoculation of NOD/SCID mice with CD34 + hematopoietic progenitor cells and stem cells (CD34 + HP/HSCs) infected ex vivo with HTLV-1. HTLV-1-HU-NOD/SCIDmice consistently developed CD4 + CD25 + T cell lymphomas with clinical characteristics associated with ATLL and infected mice showed hyperproliferation of infected human stem cells (CD34 + CD38 − ) in the bone marrow. Inoculation of NOD/SCID mice withCD34 + HP/HSCs transduced with a lentivirus vector (LV) expressing the HTLV-1oncoprotein (Tax1) also developed CD4 + CD25 + lymphomas. The HTLV-1 bZIP protein(HBZ), encoded by the minus strand of the HTLV-1 genome, is expressed in all ATLL cells and has been implicated in the maintenance of leukemogenesis. HBZ has previously been previously shown to interact with numerous cellular factors and can modulate Tax1 activity in vitro . To establish the role of HBZ in HTLV-1 replication and leukemogenesis in vivo , HU-SCID mice were infected with an infectious proviral clone lacking functional HBZ (HTLV-1ΔHBZ). HTLV-1ΔHBZ-infected HU-SCID mice developed lymphoproliferations with an immature preleukemic CD4 − CD8 − CD90 + phenotype starting at ~10 weeks post-reconstitution. In contrast wild type HTLV-1 Infection reproducibly induces a mature CD4 + CD25 + CD90 − lymphoma. Lymphoma cells successfully engrafted naive NOD/SCID mice when injected into the peritoneal cavity and these cells maintain the expression of viral proteins, gp46 env and p19 gag . HTLV-1 Infection of CD34 + HP/HSCs and the recapitulation of a lymphoma similar to ATLL in HU-NOD/SCID mice suggest that hematopoietic stem cells provide a relevant cellular target and viral reservoir in vivo and that Infection of these cells contribute to viral lymphomagenesis in humans. The HTLV-1-HU-SCID mouse model presents a compelling in vivo model to characterize molecular initiation and progression of events in the generation of ATL and to establish the role of HTLV-1 auxiliary proteins in viral pathogenesis.