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Retrovirology Dec 2019The extraordinarily high prevalence of HTLV-1 subtype C (HTLV-1C) in some isolated indigenous communities in Oceania and the severity of the health conditions associated... (Review)
Review
The extraordinarily high prevalence of HTLV-1 subtype C (HTLV-1C) in some isolated indigenous communities in Oceania and the severity of the health conditions associated with the virus impress the great need for basic and translational research to prevent and treat HTLV-1 infection. The genome of the virus's most common subtype, HTLV-1A, encodes structural, enzymatic, and regulatory proteins that contribute to viral persistence and pathogenesis. Among these is the p30 protein encoded by the doubly spliced Tax-orf II mRNA, a nuclear/nucleolar protein with both transcriptional and post-transcriptional activity. The p30 protein inhibits the productive replication cycle via nuclear retention of the mRNA that encodes for both the viral transcriptional trans-activator Tax, and the Rex proteins that regulate the transport of incompletely spliced viral mRNA to the cytoplasm. In myeloid cells, p30 inhibits the PU-1 transcription factor that regulates interferon expression and is a critical mediator of innate and adaptive immunity. Furthermore, p30 alters gene expression, cell cycle progression, and DNA damage responses in T-cells, raising the hypothesis that p30 may directly contribute to T cell transformation. By fine-tuning viral expression while also inhibiting host innate responses, p30 is likely essential for viral infection and persistence. This concept is supported by the finding that macaques, a natural host for the closely genetically related simian T-cell leukemia virus 1 (STLV-1), exposed to an HTLV-1 knockout for p30 expression by a single point mutation do not became infected unless reversion and selection of the wild type HTLV-1 genotype occurs. All together, these data suggest that inhibition of p30 may help to curb and eventually eradicate viral infection by exposing infected cells to an effective host immune response.
Topics: Animals; Cell Line; Gene Expression; Gene Expression Regulation, Viral; Genotype; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Macaca; RNA, Viral; Retroviridae Proteins; Virus Latency
PubMed: 31852501
DOI: 10.1186/s12977-019-0501-2 -
The Lancet. Infectious Diseases Apr 2020
Topics: Epidemiologic Studies; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Outcome Assessment, Health Care
PubMed: 32222206
DOI: 10.1016/S1473-3099(20)30133-X -
The Lancet. Infectious Diseases Apr 2020
Topics: Epidemiologic Studies; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Outcome Assessment, Health Care
PubMed: 32222205
DOI: 10.1016/S1473-3099(20)30043-8 -
Viruses Aug 2022The bovine leukemia virus (BLV) and the human T-lymphothropic viruses (HTLVs) are members of the deltaretrovirus genus of family. An essential event of the retroviral...
The bovine leukemia virus (BLV) and the human T-lymphothropic viruses (HTLVs) are members of the deltaretrovirus genus of family. An essential event of the retroviral life cycle is the processing of the polyproteins by the viral protease (PR); consequently, these enzymes became important therapeutic targets of the anti-retroviral drugs. As compared to human immunodeficiency viruses (HIVs), the deltaretroviruses have a different replication strategy, as they replicate predominantly in the DNA form, by forcing the infected cell to divide, unlike HIV-1, which replicates mainly by producing a vast number of progeny virions and by reinfection. Due to bypassing the error-prone reverse transcription step of replication, the PRs of deltaretroviruses did not undergo such extensive evolution as HIV PRs and remained more highly conserved. In this work, we studied the abilities of wild-type and modified BLV, HTLV (type 1, 2 and 3), and HIV-1 PRs (fused to an N-terminal MBP tag) for self-processing. We designed a cleavage site mutant MBP-fused BLV PR precursor as well, this recombinant enzyme was unable for self-proteolysis, the MBP fusion tag decreased its catalytic efficiency but showed an unusually low K for the IB-268 protease inhibitor. Our results show that the HTLV and BLV deltaretrovirus PRs exhibit lower mutation tolerance as compared to HIV-1 PR, and are less likely to retain their activity upon point mutations at various positions, indicating a higher flexibility of HIV-1 PR in tolerating mutations under selective pressure.
Topics: Deltaretrovirus; Endopeptidases; HIV Infections; HIV Protease; HIV Seropositivity; HIV-1; Humans; Leukemia Virus, Bovine; Mutation; Peptide Hydrolases; Polyproteins; Protease Inhibitors
PubMed: 36146695
DOI: 10.3390/v14091888 -
PLoS Pathogens Apr 2022We investigated the impact of monocytes, NK cells, and CD8+ T-cells in primary HTLV-1 infection by depleting cell subsets and exposing macaques to either HTLV-1 wild...
We investigated the impact of monocytes, NK cells, and CD8+ T-cells in primary HTLV-1 infection by depleting cell subsets and exposing macaques to either HTLV-1 wild type (HTLV-1WT) or to the HTLV-1p12KO mutant unable to infect replete animals due to a single point mutation in orf-I that inhibits its expression. The orf-I encoded p8/p12 proteins counteract cytotoxic NK and CD8+ T-cells and favor viral DNA persistence in monocytes. Double NK and CD8+ T-cells or CD8 depletion alone accelerated seroconversion in all animals exposed to HTLV-1WT. In contrast, HTLV-1p12KO infectivity was fully restored only when NK cells were also depleted, demonstrating a critical role of NK cells in primary infection. Monocyte/macrophage depletion resulted in accelerated seroconversion in all animals exposed to HTLV-1WT, but antibody titers to the virus were low and not sustained. Seroconversion did not occur in most animals exposed to HTLV-1p12KO. In vitro experiments in human primary monocytes or THP-1 cells comparing HTLV-1WT and HTLV-1p12KO demonstrated that orf-I expression is associated with inhibition of inflammasome activation in primary cells, with increased CD47 "don't-eat-me" signal surface expression in virus infected cells and decreased monocyte engulfment of infected cells. Collectively, our data demonstrate a critical role for innate NK cells in primary infection and suggest a dual role of monocytes in primary infection. On one hand, orf-I expression increases the chances of viral transmission by sparing infected cells from efferocytosis, and on the other may protect the engulfed infected cells by modulating inflammasome activation. These data also suggest that, once infection is established, the stoichiometry of orf-I expression may contribute to the chronic inflammation observed in HTLV-1 infection by modulating monocyte efferocytosis.
Topics: Animals; HTLV-I Infections; Human T-lymphotropic virus 1; Inflammasomes; Killer Cells, Natural; Monocytes
PubMed: 35377924
DOI: 10.1371/journal.ppat.1010416 -
Journal of Investigative Medicine High... 2021Adult T-cell leukemia/lymphoma is an aggressive T-cell malignancy caused by the long-term infection of human T-cell lymphotropic virus type 1 (HTLV-1). Our understanding...
Adult T-cell leukemia/lymphoma is an aggressive T-cell malignancy caused by the long-term infection of human T-cell lymphotropic virus type 1 (HTLV-1). Our understanding of clinical features still largely relies on the Shimoyama classification developed 30 years ago, which described the 4 clinical subtypes (the smoldering, chronic, lymphoma, and acute types) based on the manifestations of lymphocytosis, elevated lactate dehydrogenase, hypercalcemia, lymphadenopathy, and involvement of the skin, lung, liver, spleen, central nervous system, bone, ascites, pleural effusion, and gastrointestinal tract. HTLV-1-associated lymphoma has a variety of presentations but the presentation of massive lymphadenopathy and compression symptoms is rare and has not been emphasized in the literature. In this article, we describe 2 cases of adult T-cell leukemia/lymphomas that presented with massive cervical nodes or mediastinal nodes with compressing symptoms as the major presenting clinical features. Clinicians should remain aware of this type of presentation by HTLV-1-associated lymphoma, especially in patients who came from endemic areas, even if not all clinical features are present and particularly with hypercalcemia and lytic bone lesions.
Topics: Human T-lymphotropic virus 1; Humans; Leukemia-Lymphoma, Adult T-Cell; Lymphadenopathy; Lymphoma; Skin
PubMed: 33969717
DOI: 10.1177/23247096211013235 -
Seminars in Diagnostic Pathology Mar 2020
Review
Topics: Eye Diseases; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Nervous System Diseases
PubMed: 31387754
DOI: 10.1053/j.semdp.2019.07.011 -
Preventive Veterinary Medicine Mar 2022A high herd and within-herd prevalence of Bovine Leukemia Virus (BLV) infections in the dairy herds of North America and the negative effects thereof caused the Alberta...
A high herd and within-herd prevalence of Bovine Leukemia Virus (BLV) infections in the dairy herds of North America and the negative effects thereof caused the Alberta dairy industry to initiate the development of an on farm BLV control program. Because BLV control is dependent on the commitment of the farmer, potential barriers were identified and farmers' and veterinarians' points of view toward different control options were investigated to inform how the control program might be adjusted. Conversations with these stakeholders were sought and four focus groups with farmers and eleven interviews with veterinarians were conducted. Testing for BLV, the most common BLV control strategies (testing/culling/segregation/management), as well as on farm best management practices (BMP) to prevent the transmission of BLV, were discussed. The thematic analysis of these conversations resulted in the following findings: Testing of animals was considered important for BLV control, but the financial investment was prohibitive for farmers. Test and cull as well as test and segregation approaches of test positive animals were considered efficient BLV control measures, but impractical and not feasible due to the supply managed Alberta dairy industry (i.e. milk is produced based on demand), with a high prevalence. The management of test positive animals with BMP to prevent new infections and thereby decreasing the within-herd prevalence was considered the only realistic BLV control strategy. The most important barriers for suggested BMP were the cost for some BMP, the inconvenience of performing other BMP, as well as difficulties in performing some BMP consistently and well. Additionally, a lack of knowledge about BLV and its control were identified as an important barrier. On the contrary, farmers indicated being inclined to implement BMP they considered feasible or that were considered a standard within the industry. Further, if BMP increased convenience on farm, they were considered easy to implement. Farmers and veterinarians agreed in many, but not all cases. For example, the single use of examination sleeves was met with differing opinions (i.e. considered doable by farmers while veterinarians assumed it to be too costly). In conclusion, stakeholders' awareness and communication amongst each other (e.g. veterinarians and farmers) about BLV and its control has to be highlighted in order to manage BLV infection successfully. In addition, by communicating and understanding barriers and motivators for specific BMP, important barriers could be identified (e.g. difficulties while changing needles), and solutions found (e.g. tool belt for needles), thereby improving BLV control efforts on farm.
Topics: Alberta; Animals; Dairying; Farmers; Humans; Leukemia Virus, Bovine; Veterinarians
PubMed: 35158251
DOI: 10.1016/j.prevetmed.2022.105590 -
Frontiers in Public Health 2022Human T-lymphotropic viruses 1 and 2 (HTLV-1 and HTLV-2) are retroviruses that originated on the African continent and dispersed throughout other continents through...
Human T-lymphotropic viruses 1 and 2 (HTLV-1 and HTLV-2) are retroviruses that originated on the African continent and dispersed throughout other continents through human migratory flows. This study describes the prevalence of HTLV-1 and HTLV-2 infection in residents of 11 quilombo remnant communities in the state of Pará, Brazil, and the associated risk factors. A total of 859 individuals (334 men and 525 women), aged between 7 and 91 years, participated in the study. All subjects answered a questionnaire with questions on sociodemographic characteristics and on risk factors associated with HTLV infection, and blood samples were collected and separated into plasma and leukocytes. An immunoenzymatic assay (ELISA; Murex HTLV-I+II, DiaSorin, Dartford, UK) was used as a screening test, and positive samples were subjected to line immunoassay confirmatory tests (Inno-LIA HTLV I/II Score FUJIREBIO) and DNA extraction for subsequent real-time PCR to differentiate the viral type. Four of the 859 individuals were seropositive for HTLV. HTLV-1 infection was confirmed in one individual from the Itamoari community (0.92%), and HTLV-2 infection was confirmed in two individuals from São Benedito (3.17%) and in one individual from Arimandeua (2.22%). Blood transfusion was the only risk factor associated with HTLV infection in this study. This study reports the occurrence of HTLV-1 and HTLV-2 in quilombo remnant communities in the state of Pará. Considering the African origin of the virus and its introduction into Brazil from the slave trade, the continued evaluation of quilombola communities in the state of Pará is essential to better characterize the distribution of infections in these populations and to create public health policies for the control of the spread of the virus and associated diseases.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brazil; Child; Female; HTLV-I Infections; HTLV-II Infections; Human T-lymphotropic virus 1; Human T-lymphotropic virus 2; Humans; Male; Middle Aged; Prevalence; Risk Factors; Young Adult
PubMed: 35433598
DOI: 10.3389/fpubh.2022.871865 -
Journal of the American Academy of... May 2023The Epstein-Barr virus (EBV) is a DNA virus that infects 90% of the human population, is responsible for certain cutaneous lymphomas (extranodal NK/T-cell lymhoma,... (Review)
Review
The Epstein-Barr virus (EBV) is a DNA virus that infects 90% of the human population, is responsible for certain cutaneous lymphomas (extranodal NK/T-cell lymhoma, hydroa vacciniforme lymphoproliferative disorder, lymphomatoid granulomatosis, others), and can be associated with a variety of cutaneous manifestations (eg, infectious mononucleosis, severe mosquito bite allergy, chronic active EBV disease, Gianotti-Crosti syndrome). EBV-related skin disorders are frequent in certain populations (South and Cental America, Africa, Asia, and Oceania) and can be diagnostically challenging. The human T-lymphotropic virus type-1 is a retrovirus, which is known to be associated with adult T-cell leukemia/lymphoma, neurologic disorders, but also cutaneous non-neoplastic manifestations (infective dermatitis, infections, and infestations). We performed an updated revision of the clinical dermatologic and histopathologic findings associated with the cutaneous non-neoplastic and preneoplastic disorders occurring in association with the EBV and human T-lymphotropic virus type-1.
Topics: Humans; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Human T-lymphotropic virus 1; Skin; Lymphoproliferative Disorders
PubMed: 36049582
DOI: 10.1016/j.jaad.2022.07.063