High level of genomic divergence in orf-I p12 and hbz genes of HTLV-1 subtype-C in Central Australia.
Human T-lymphotropic virus 1
/ genetics
Humans
HTLV-I Infections
/ virology
Australia
Phylogeny
Retroviridae Proteins
/ genetics
Genetic Variation
Adult
Genome, Viral
Viral Regulatory and Accessory Proteins
/ genetics
Sequence Analysis, DNA
Male
Female
Middle Aged
DNA, Viral
/ genetics
Viral Proteins
/ genetics
Basic-Leucine Zipper Transcription Factors
Journal
Retrovirology
ISSN: 1742-4690
Titre abrégé: Retrovirology
Pays: England
ID NLM: 101216893
Informations de publication
Date de publication:
17 Jul 2024
17 Jul 2024
Historique:
received:
18
03
2024
accepted:
12
06
2024
medline:
17
7
2024
pubmed:
17
7
2024
entrez:
16
7
2024
Statut:
epublish
Résumé
Human T cell lymphotropic virus type 1 (HTLV-1) infection remains a largely neglected public health problem, particularly in resource-poor areas with high burden of communicable and non-communicable diseases, such as some remote populations in Central Australia where an estimated 37% of adults are infected with HTLV-1. Most of our understanding of HTLV-1 infection comes from studies of the globally spread subtype-A (HTLV-1a), with few molecular studies reported with the Austral-Melanesian subtype-C (HTLV-1c) predominant in the Indo-Pacific and Oceania regions. Using a primer walking strategy and direct sequencing, we constructed HTLV-1c genomic consensus sequences from 22 First Nations participants living with HTLV-1c in Central Australia. Phylogenetic and pairwise analysis of this subtype-C proviral gDNA showed higher levels of genomic divergence in comparison to previously published HTLV-1a genomes. While the overall genomic homology between subtypes was 92.5%, the lowest nucleotide and amino acid sequence identity occurred near the 3' end of the proviral genome coding regulatory genes, especially overlapping hbz (85.37%, 77.46%, respectively) and orf-I product p12 (82.00%, 70.30%, respectively). Strikingly, the HTLV-1c genomic consensus sequences uniformly showed a defective translation start codon for the immune regulatory proteins p12/p8 encoded by the HTLV-1A orf-I. Deletions in the proviral genome were detected in many subjects, particularly in the structural gag, pol and env genes. Similarly, using a droplet digital PCR assay measuring the copies of gag and tax per reference host genome, we quantitatively confirmed that provirus retains the tax gene region at higher levels than gag. Our genomic analysis of HTLV-1c in Central Australia in conjunction with earlier Melanesian HTLV-1c sequences, elucidate substantial differences with respect to the globally spread HTLV-1a. Future studies should address the impact these genomic differences have on infection and the regionally distinctive frequency of associated pulmonary disease. Understanding the host and virus subtype factors which contribute to the differential morbidity observed, is crucial for the development of much needed therapeutics and vaccine strategies against this highly endemic infection in remote First Nations communities in Central Australia.
Sections du résumé
BACKGROUND
BACKGROUND
Human T cell lymphotropic virus type 1 (HTLV-1) infection remains a largely neglected public health problem, particularly in resource-poor areas with high burden of communicable and non-communicable diseases, such as some remote populations in Central Australia where an estimated 37% of adults are infected with HTLV-1. Most of our understanding of HTLV-1 infection comes from studies of the globally spread subtype-A (HTLV-1a), with few molecular studies reported with the Austral-Melanesian subtype-C (HTLV-1c) predominant in the Indo-Pacific and Oceania regions.
RESULTS
RESULTS
Using a primer walking strategy and direct sequencing, we constructed HTLV-1c genomic consensus sequences from 22 First Nations participants living with HTLV-1c in Central Australia. Phylogenetic and pairwise analysis of this subtype-C proviral gDNA showed higher levels of genomic divergence in comparison to previously published HTLV-1a genomes. While the overall genomic homology between subtypes was 92.5%, the lowest nucleotide and amino acid sequence identity occurred near the 3' end of the proviral genome coding regulatory genes, especially overlapping hbz (85.37%, 77.46%, respectively) and orf-I product p12 (82.00%, 70.30%, respectively). Strikingly, the HTLV-1c genomic consensus sequences uniformly showed a defective translation start codon for the immune regulatory proteins p12/p8 encoded by the HTLV-1A orf-I. Deletions in the proviral genome were detected in many subjects, particularly in the structural gag, pol and env genes. Similarly, using a droplet digital PCR assay measuring the copies of gag and tax per reference host genome, we quantitatively confirmed that provirus retains the tax gene region at higher levels than gag.
CONCLUSIONS
CONCLUSIONS
Our genomic analysis of HTLV-1c in Central Australia in conjunction with earlier Melanesian HTLV-1c sequences, elucidate substantial differences with respect to the globally spread HTLV-1a. Future studies should address the impact these genomic differences have on infection and the regionally distinctive frequency of associated pulmonary disease. Understanding the host and virus subtype factors which contribute to the differential morbidity observed, is crucial for the development of much needed therapeutics and vaccine strategies against this highly endemic infection in remote First Nations communities in Central Australia.
Identifiants
pubmed: 39014486
doi: 10.1186/s12977-024-00647-w
pii: 10.1186/s12977-024-00647-w
doi:
Substances chimiques
Retroviridae Proteins
0
HBZ protein, human T-cell leukemia virus type I
0
p12I protein, Human T-lymphotropic virus 1
0
Viral Regulatory and Accessory Proteins
0
DNA, Viral
0
Viral Proteins
0
Basic-Leucine Zipper Transcription Factors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
14Subventions
Organisme : National Health and Medical Research Council
ID : GNT2004670
Organisme : National Health and Medical Research Council
ID : GNT1176574
Informations de copyright
© 2024. The Author(s).
Références
Gessain A, Cassar O. Epidemiological aspects and world distribution of HTLV-1 infection. Front Microbiol. 2012;3:388.
doi: 10.3389/fmicb.2012.00388
pubmed: 23162541
pmcid: 3498738
Gessain A, Ramassamy JL, Afonso PV, Cassar O. Geographic distribution, clinical epidemiology and genetic diversity of the human oncogenic retrovirus HTLV-1 in Africa, the world’s largest endemic area. Front Immunol. 2023;14:1043600.
doi: 10.3389/fimmu.2023.1043600
pubmed: 36817417
pmcid: 9935834
Cassar O, Einsiedel L, Afonso PV, Gessain A. Human T-cell lymphotropic virus type 1 subtype C molecular variants among indigenous australians: new insights into the molecular epidemiology of HTLV-1 in Australo-Melanesia. PLoS Negl Trop Dis. 2013;7: e2418.
doi: 10.1371/journal.pntd.0002418
pubmed: 24086779
pmcid: 3784485
Osame M, Igata A. The history of discovery and clinico-epidemiology of HTLV-I-associated myelopathy(HAM). Jpn J Med. 1989;28:412–4.
doi: 10.2169/internalmedicine1962.28.412
pubmed: 2739154
Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA. 1980;77:7415–9.
doi: 10.1073/pnas.77.12.7415
pubmed: 6261256
pmcid: 350514
Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood. 1977;50:481–92.
doi: 10.1182/blood.V50.3.481.481
pubmed: 301762
Schierhout G, McGregor S, Gessain A, Einsiedel L, Martinello M, Kaldor J. Association between HTLV-1 infection and adverse health outcomes: a systematic review and meta-analysis of epidemiological studies. Lancet Infect Dis. 2020;20:133–43.
doi: 10.1016/S1473-3099(19)30402-5
pubmed: 31648940
Einsiedel L, Chiong F, Jersmann H, Taylor GP. Human T-cell leukaemia virus type 1 associated pulmonary disease: clinical and pathological features of an under-recognised complication of HTLV-1 infection. Retrovirology. 2021;18:1.
doi: 10.1186/s12977-020-00543-z
pubmed: 33407607
pmcid: 7789585
Kimura I, Tsubota T, Tada S, Sogawa J. Presence of antibodies against adult T cell leukemia antigen in the patients with chronic respiratory diseases. Acta Med Okayama. 1986;40:281–4.
pubmed: 3493619
Einsiedel L, Cassar O, Goeman E, Spelman T, Au V, Hatami S, Joseph S, Gessain A. Higher human T-lymphotropic virus type 1 subtype C proviral loads are associated with bronchiectasis in indigenous australians: results of a case-control study. Open Forum Infect Dis. 2014;1:ofu023.
doi: 10.1093/ofid/ofu023
pubmed: 25734096
pmcid: 4324180
Einsiedel L, Fernandes L, Spelman T, Steinfort D, Gotuzzo E. Bronchiectasis is associated with human T-lymphotropic virus 1 infection in an Indigenous Australian population. Clin Infect Dis. 2012;54:43–50.
doi: 10.1093/cid/cir766
pubmed: 22095566
Einsiedel L, Pham H, Wilson K, Walley R, Turpin J, Bangham C, Gessain A, Woodman RJ. Human T-Lymphotropic Virus type 1c subtype proviral loads, chronic lung disease and survival in a prospective cohort of Indigenous Australians. PLoS Negl Trop Dis. 2018;12: e0006281.
doi: 10.1371/journal.pntd.0006281
pubmed: 29529032
pmcid: 5874075
Einsiedel LJ, Woodman RJ. Two nations: racial disparities in bloodstream infections recorded at Alice Springs Hospital, central Australia, 2001–2005. Med J Aust. 2010;192:567–71.
doi: 10.5694/j.1326-5377.2010.tb03638.x
pubmed: 20477732
Einsiedel L, Cassar O, Spelman T, Joseph S, Gessain A. Higher HTLV-1c proviral loads are associated with blood stream infections in an Indigenous Australian population. J Clin Virol. 2016;78:93–8.
doi: 10.1016/j.jcv.2016.03.006
pubmed: 27011343
Talukder MRR, Walley R, Pham H, Schinke S, Woodman R, Wilson K, Sajiv C, Einsiedel L. Higher human T-cell leukaemia virus type 1 (HTLV-1) proviral load is associated with end-stage kidney disease in Indigenous Australians: results of a case-control study in central Australia. J Med Virol. 2019;91:1866–72.
doi: 10.1002/jmv.25532
pubmed: 31254397
Talukder MR, Woodman R, Pham H, Wilson K, Gessain A, Kaldor J, Einsiedel L. High human T-cell leukemia virus type 1c proviral loads are associated with diabetes and chronic kidney disease: results of a cross-sectional community survey in Central Australia. Clin Infect Dis. 2023;76:e820–6.
doi: 10.1093/cid/ciac614
pubmed: 35903021
Hirons A, Khoury G, Purcell DFJ. Human T-cell lymphotropic virus type-1: a lifelong persistent infection, yet never truly silent. Lancet Infect Dis. 2020. https://doi.org/10.1016/S1473-3099(20)30328-5 .
doi: 10.1016/S1473-3099(20)30328-5
pubmed: 32986997
Matsuzaki T, Nakagawa M, Nagai M, Usuku K, Higuchi I, Arimura K, Kubota H, Izumo S, Akiba S, Osame M. HTLV-I proviral load correlates with progression of motor disability in HAM/TSP: analysis of 239 HAM/TSP patients including 64 patients followed up for 10 years. J Neurovirol. 2001;7:228–34.
doi: 10.1080/13550280152403272
pubmed: 11517397
Nagai M, Usuku K, Matsumoto W, Kodama D, Takenouchi N, Moritoyo T, Hashiguchi S, Ichinose M, Bangham CR, Izumo S, Osame M. Analysis of HTLV-I proviral load in 202 HAM/TSP patients and 243 asymptomatic HTLV-I carriers: high proviral load strongly predisposes to HAM/TSP. J Neurovirol. 1998;4:586–93.
doi: 10.3109/13550289809114225
pubmed: 10065900
Okayama A, Stuver S, Matsuoka M, Ishizaki J, Tanaka G, Kubuki Y, Mueller N, Hsieh CC, Tachibana N, Tsubouchi H. Role of HTLV-1 proviral DNA load and clonality in the development of adult T-cell leukemia/lymphoma in asymptomatic carriers. Int J Cancer. 2004;110:621–5.
doi: 10.1002/ijc.20144
pubmed: 15122598
Arnold J, Zimmerman B, Li M, Lairmore MD, Green PL. Human T-cell leukemia virus type-1 antisense-encoded gene, Hbz, promotes T-lymphocyte proliferation. Blood. 2008;112:3788–97.
doi: 10.1182/blood-2008-04-154286
pubmed: 18689544
pmcid: 2572803
Fochi S, Mutascio S, Bertazzoni U, Zipeto D, Romanelli MG. HTLV deregulation of the NF-kappaB pathway: an update on tax and antisense proteins role. Front Microbiol. 2018;9:285.
doi: 10.3389/fmicb.2018.00285
pubmed: 29515558
pmcid: 5826390
Matsuoka M, Yasunaga J. Human T-cell leukemia virus type 1: replication, proliferation and propagation by Tax and HTLV-1 bZIP factor. Curr Opin Virol. 2013;3:684–91.
doi: 10.1016/j.coviro.2013.08.010
pubmed: 24060211
Mitobe Y, Yasunaga J, Furuta R, Matsuoka M. HTLV-1 bZIP factor RNA and protein impart distinct functions on T-cell proliferation and survival. Cancer Res. 2015;75:4143.
doi: 10.1158/0008-5472.CAN-15-0942
pubmed: 26383166
Pise-Masison CA, de Castro-Amarante MF, Enose-Akahata Y, Buchmann RC, Fenizia C, Washington Parks R, Edwards D, Fiocchi M, Alcantara LC Jr, Bialuk I, et al. Co-dependence of HTLV-1 p12 and p8 functions in virus persistence. PLoS Pathog. 2014;10: e1004454.
doi: 10.1371/journal.ppat.1004454
pubmed: 25375128
pmcid: 4223054
Sarkis S, Galli V, Moles R, Yurick D, Khoury G, Purcell DFJ, Franchini G, Pise-Masison CA. Role of HTLV-1 orf-I encoded proteins in viral transmission and persistence. Retrovirology. 2019;16:43.
doi: 10.1186/s12977-019-0502-1
pubmed: 31852543
pmcid: 6921521
Gessain A, Boeri E, Yanagihara R, Gallo RC, Franchini G. Complete nucleotide sequence of a highly divergent human T-cell leukemia (lymphotropic) virus type I (HTLV-I) variant from melanesia: genetic and phylogenetic relationship to HTLV-I strains from other geographical regions. J Virol. 1993;67:1015–23.
doi: 10.1128/jvi.67.2.1015-1023.1993
pubmed: 8419636
pmcid: 237456
Einsiedel L, Pham H, Au V, Hatami S, Wilson K, Spelman T, Jersmann H. Predictors of non-cystic fibrosis bronchiectasis in Indigenous adult residents of central Australia: results of a case-control study. ERJ Open Res. 2019;5:1.
doi: 10.1183/23120541.00001-2019
Chiong F, Jersmann H, Wilson K, Einsiedel L. HTLV-1c associated bronchiolitis in an Aboriginal man from central Australia. IDCases. 2020;19: e00714.
doi: 10.1016/j.idcr.2020.e00714
pubmed: 32123663
pmcid: 7037585
Ibrahim F, de Thé G, Gessain A. 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. J Virol. 1995;69:6980–93.
doi: 10.1128/jvi.69.11.6980-6993.1995
pubmed: 7474117
pmcid: 189617
Van Dooren S, Pybus OG, Salemi M, Liu HF, Goubau P, Remondegui C, Talarmin A, Gotuzzo E, Alcantara LC, Galvao-Castro B, Vandamme AM. The low evolutionary rate of human T-cell lymphotropic virus type-1 confirmed by analysis of vertical transmission chains. Mol Biol Evol. 2004;21:603–11.
doi: 10.1093/molbev/msh053
pubmed: 14739252
Nakao K, Ohba N, Matsumoto M. Noninfectious anterior uveitis in patients infected with human T-lymphotropic virus type I. Jpn J Ophthalmol. 1989;33:472–81.
pubmed: 2576286
Yurick D, Khoury G, Clemens B, Loh L, Pham H, Kedzierska K, Einsiedel L, Purcell D. Multiplex droplet digital PCR assay for quantification of human T-cell leukemia virus type 1 subtype c DNA proviral load and T cells from blood and respiratory exudates sampled in a remote setting. J Clin Microbiol. 2019;57:e01063-e11018.
doi: 10.1128/JCM.01063-18
pubmed: 30518541
pmcid: 6355533
da Costa CA, Furtado KC, Ferreira Lde S, Almeida Dde S, Linhares Ada C, Ishak R, Vallinoto AC, de Lemos JA, Martins LC, Ishikawa EA, et al. Familial transmission of human T-cell lymphotrophic virus: silent dissemination of an emerging but neglected infection. PLoS Negl Trop Dis. 2013;7: e2272.
doi: 10.1371/journal.pntd.0002272
pubmed: 23785534
pmcid: 3681619
Martin F, Fedina A, Youshya S, Taylor GP. A 15-year prospective longitudinal study of disease progression in patients with HTLV-1 associated myelopathy in the UK. J Neurol Neurosurg Psychiatry. 2010;81:1336–40.
doi: 10.1136/jnnp.2009.191239
pubmed: 20660921
Felber BK, Paskalis H, Kleinman-Ewing C, Wong-Staal F, Pavlakis GN. The pX protein of HTLV-I is a transcriptional activator of its long terminal repeats. Science. 1985;229:675–9.
doi: 10.1126/science.2992082
pubmed: 2992082
Arnold J, Yamamoto B, Li M, Phipps AJ, Younis I, Lairmore MD, Green PL. Enhancement of infectivity and persistence in vivo by HBZ, a natural antisense coded protein of HTLV-1. Blood. 2006;107:3976–82.
doi: 10.1182/blood-2005-11-4551
pubmed: 16424388
pmcid: 1895283
Gaudray G, Gachon F, Basbous J, Biard-Piechaczyk M, Devaux C, Mesnard JM. The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription. J Virol. 2002;76:12813–22.
doi: 10.1128/JVI.76.24.12813-12822.2002
pubmed: 12438606
pmcid: 136662
Pise-Masison CA, Franchini G. Hijacking host immunity by the human T-cell leukemia virus type-1: implications for therapeutic and preventive vaccines. Viruses. 2022;14:2084.
doi: 10.3390/v14102084
pubmed: 36298639
pmcid: 9609126
Katsuya H, Islam S, Tan BJY, Ito J, Miyazato P, Matsuo M, Inada Y, Iwase SC, Uchiyama Y, Hata H, et al. The nature of the HTLV-1 provirus in naturally infected individuals analyzed by the viral DNA-capture-seq approach. Cell Rep. 2019;29:724-735.e724.
doi: 10.1016/j.celrep.2019.09.016
pubmed: 31618639
Cook LB, Melamed A, Niederer H, Valganon M, Laydon D, Foroni L, Taylor GP, Matsuoka M, Bangham CR. The role of HTLV-1 clonality, proviral structure, and genomic integration site in adult T-cell leukemia/lymphoma. Blood. 2014;123:3925–31.
doi: 10.1182/blood-2014-02-553602
pubmed: 24735963
pmcid: 4064332
Cook LB, Rowan AG, Melamed A, Taylor GP, Bangham CR. HTLV-1-infected T cells contain a single integrated provirus in natural infection. Blood. 2012;120:3488–90.
doi: 10.1182/blood-2012-07-445593
pubmed: 22955925
pmcid: 3482858
Gouy M, Guindon S, Gascuel O. SeaView version 4: a multiplatform graphical user interface for sequence alignment and phylogenetic tree building. Mol Biol Evol. 2010;27:221–4.
doi: 10.1093/molbev/msp259
pubmed: 19854763
Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K, Li W, Lopez R, McWilliam H, Remmert M, Söding J, et al. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol Syst Biol. 2011;7:539.
doi: 10.1038/msb.2011.75
pubmed: 21988835
pmcid: 3261699
Tamura K, Nei M. Estimation of the number of nucleotide substitutions in the control region of mitochondrial DNA in humans and chimpanzees. Mol Biol Evol. 1993;10:512–26.
pubmed: 8336541
Tamura K, Stecher G, Kumar S. MEGA11: molecular evolutionary genetics analysis version 11. Mol Biol Evol. 2021;38:3022–7.
doi: 10.1093/molbev/msab120
pubmed: 33892491
pmcid: 8233496
Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990;215:403–10.
doi: 10.1016/S0022-2836(05)80360-2
pubmed: 2231712
Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K, Bates R, Žídek A, Potapenko A, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596:583–9.
doi: 10.1038/s41586-021-03819-2
pubmed: 34265844
pmcid: 8371605
Varadi M, Anyango S, Deshpande M, Nair S, Natassia C, Yordanova G, Yuan D, Stroe O, Wood G, Laydon A, et al. AlphaFold protein structure database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res. 2021;50:D439–44.
doi: 10.1093/nar/gkab1061
pmcid: 8728224
Schrodinger, LLC: The PyMOL molecular graphics system, version 2.5.7.1. 2015.