Human T-Lymphotropic Virus type 1 (HTLV-1): a primer

Posted onAuthorIan M Mackay, PhD (EIC)

What is HTLV-1?

HTLV-1 is a human delta retrovirus assigned to the genus Deltaretrovirus, species Primate T-lymphotropic virus 1 [5]. It was first described in 1980.[10]

ViralZone:www.expasy.org/viralzone,
SIB Swiss Institute of Bioinformatics [6]

Soon thereafter Japanese researchers identified endemic virus, especially in southwestern Japan.[8,9]

HTLV-1 infects a cell and makes new DNA from its RNA genetic blueprint using an enzyme called reverse transcriptase.[7] This DNA then acts as a blueprint to manufacture more RNA and then viral proteins. The DNA form inserts into a random site in the host cell genome.[19] This form of HTLV-1 is called the provirus.

The order of making RNA first then DNA is the reverse (retro) of the usual ‘direction’ of protein manufacture in human cells which is from DNA to RNA to protein.

HTLV-1 infects T and B lymphocytes, monocytes, endothelial cells, and fibroblasts. The virus uses a ubiquitous cell surface molecule, the glucose transporter 1, as its receptor.[12]

HTLV-1 is established mostly in resource-limited regions of the world, infecting an estimated 10-20 million people.[9] Australia hosts the distinct HTLV-1c strain although little is known about its distribution.[1,17] It is predicted that HTLV-1c arrived and then divided into at least 2 further distinct groups (clades) around 3,000-9,000 years ago.[17,18]

In Australia, HTLV-1 infection occurs in the middle of the country (‘central Australia’). This is mostly described from the Northern Territory but also Western Australia and South Australia. Antibodies were detected in sera collected in 1956 from Aboriginal Australians in Cape York, Queensland.[20] In some communities, greater than 40% of Aboriginal Australian adults are HTLV-1 infected.[13]

An HTLV-1 timeline. Some discoveries of interest are shown. Click to enlarge.

What does HTLV-1 do?

Infection is generally without symptoms. Between 3-5% of those infected develop a highly malignant T-cell neoplasm known as adult T-cell leukaemia/lymphoma (ATLL).[11] This can take decades to develop. There are an estimated 23.6 ATLL cases /100,000 population among Australian adult HTLV-1 carriers.[16]

Infection can also result in HTLV-1-associated-myeIopathy/tropical-spastic-paraparesis (HAM/TSP) and other inflammatory diseases involving the lungs, central nervous system and eyes.[1,10]

Crusted scabies has also been described as a marker for HTLV-1 infection.[2,3]

Co-infection with the human gut roundworm parasite, Strongyloides stercoralis, is associated with parasite dissemination and the development of severe strongyloidiasisis.[21,22]

Bronchiectasis is the most common evidence of HTLV-1 infection among Aboriginal Australians.[1] 

How is HTLV-1 transmitted?

Epidemiological aspects and world distribution of HTLV-1 infection. Gessain & Cassar 2012. Front. Microbiol., 15 November 2012  [8]

The virus can be passed to a susceptible new host via prolonged breastfeeding, sexual transmission (4-times more frequently male to female[9]),  via HTLV-1-contaminated blood or blood-product transfusion or intravenous drug use.[8]

Japan successfully deployed a program to reduce transmission methods by reducing mother-to-child-transmission.[14]

How do we test for HTLV-1?

Antibodies to viral proteins are produced as a result of infection. Detecting these is a widely used and relatively inexpensive method that fits into the workflow of the modern serology laboratory. Specificity issues were an early issue but seem to have been overcome.[8]

The detection of proviral DNA using PCR methods is a sensitive way to identify infected blood cells. Enhanced methods can quantify how much provirus is present which is related to disease progression. A typical healthy infected person may have proviral DNA in 0.1-1% of peripheral blood cells.[10] Virus levels are generally stable but a rise has been associated with the development of HAM/TSP and proviral load is higher in bronchiectasis.[10,15] 

References…

  1. Human T-Lymphotropic Virus type 1c subtype proviral loads, chronic lung disease and survival in a prospective cohort of Indigenous Australians.
    http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006281
  2. Crusted scabies: a clinical marker of human T-lymphotropic virus type 1 infection in central Australia.
    https://www.mja.com.au/journal/2014/200/11/crusted-scabies-clinical-marker-human-t-lymphotropic-virus-type-1-infection
  3. HTLV-I and scabies in Australian Aborigines
    https://www.thelancet.com/journals/lancet/article/PII0140-6736(93)91186-P/abstract
  4. Human T-lymphotropic virus 1: recent knowledge about an ancient infection
  5. https://talk.ictvonline.org/ictv-reports/ictv_9th_report/reverse-transcribing-dna-and-rna-viruses-2011/w/rt_viruses/161/retroviridae
  6. https://viralzone.expasy.org/59
  7. Retrovirus
    https://www.britannica.com/science/retrovirus
  8. Epidemiological aspects and world distribution of HTLV-1 infection
    https://www.frontiersin.org/articles/10.3389/fmicb.2012.00388/full
  9. HTLV-1 infections
    http://jcp.bmj.com/content/53/8/581
  10. Detection and isolation of type c retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC350514/
  11. HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma—A Tale of Two Proteins: Tax and HBZ
    http://www.mdpi.com/1999-4915/8/6/161
  12. The Ubiquitous Glucose Transporter GLUT-1 Is a Receptor for HTLV
    https://doi.org/10.1016/S0092-8674(03)00881-X
  13. The prevalence and clinical associations of HTLV-1 infection in a remote Indigenous community
    https://www.mja.com.au/journal/2016/205/7/prevalence-and-clinical-associations-htlv-1-infection-remote-indigenous
  14. Establishment of the milk-borne transmission as a key factor for the peculiar endemicity of human T-lymphotropic virus type 1 (HTLV-1): the ATL Prevention Program Nagasaki
    https://www.jstage.jst.go.jp/article/pjab/87/4/87_4_152/_article
  15. Higher Human T-Lymphotropic Virus Type 1 Subtype C Proviral Loads Are Associated With
    Bronchiectasis in Indigenous Australians: Results of a Case-Control Study
    https://academic.oup.com/ofid/article-lookup/doi/10.1093/ofid/ofu023
  16. Variant Human T-cell Lymphotropic Virus Type 1c and Adult T-cell Leukemia, Australia
    https://wwwnc.cdc.gov/eid/article/19/10/13-0105_article
  17. 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
    http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0002418
  18. Detailed phylogenetic analysis of primate T-lymphotropic virus type 1 (PTLV-1) sequences from orangutans (Pongo pygmaeus) reveals new insights into the evolutionary history of PTLV-1 in Asia
    https://www.sciencedirect.com/science/article/pii/S1567134816302180
  19. Nonspecific integration of the HTLV provirus genome into adult T-cell leukaemia cells.
    https://www.ncbi.nlm.nih.gov/pubmed/6328324
  20. Antibodies to HTLV‐I in populations of the southwestern Pacific
    https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.1890260402
  21. Chronic strongyloidiasis – Don’t look and you won’t find
    https://www.racgp.org.au/afp/2016/januaryfebruary/chronic-strongyloidiasis-%E2%80%93-don%E2%80%99t-look-and-you-won%E2%80%99t-find/
  22. Epidemiological and clinical interaction between HTLV-1 and Strongyloides stercoralis
    https://www.ncbi.nlm.nih.gov/pubmed/15771684

Updates

  1. Added info and links about Strongyloides association