Guest posting: Dr Ian Marr, Senior Microbiology Registrar, Pathology North, NSW. 

Human T cell lymphotropic virus 1 (HTLV-1), the first human retrovirus discovered, is found in some PNG populations and is an important topic for M. Med. post-grads and established clinicians!

What is a retrovirus? What is the process whereby HTLV-1 infects human cells? And can you name other significant retroviruses that infect humans?

A retrovirus is a virus that has a single stranded positive sense segment of RNA. The virus carries a reverse transcriptase enzyme that  makes complementary DNA from the viral RNA once inside the host cell. This DNA is then incorporated into the host T lymphocyte genome for life.

Human T cell Lymphotrophic virus (HTLV) is in the genus Deltaretrovirus. There are currently 4 different types of HTLV. These are named sequentially, HTLV-1, HTLV-2, HTLV-3, and HTLV-4. Only HTLV1 and 2 have been seen in any large number in people, with HTLV-3 and 4 being found rarely. There is 65% correspondence between the DNA structure of HTLV-1 and HTLV-2.  Other significant retroviruses include HIV1 and HIV2!

HTLV-1/2 is 100nm in diameter and has a thin protein envelope. As detailed proviral DNA is integrated into host T lymphocyte DNA. Once these lymphocytes increase in number (e.g. in association with an inflammatory response) the HTLV viral load increases. HTLV-1/2 is unique in that it is difficult to find free viral RNA/DNA outside of the cell (unlike HIV), hence transmission of infection is thought to occur by transfer of the cells that carry virus internally. This may occur with blood product transfusion. 95% of the provirus (dsDNA) is located in CD4+ T lymphocytes, and the rest in CD8+ T cells and dendritic cells. See this article for a good explanation whereby HTLV-1/2 infects T cells.

In 1999 HTLV-1 was found in PNG in the Madang, Chimbu and Enga regions.

What were the prevalence rates in Madang from this study? Where else in the world is HTLV1 and 2 found? 

Madang had the highest prevalence from this study conducted in 1999. It showed 39 out of 267 tested were positive for HTLV-1 antibodies on Western Blott analysis.

HTLV1 and 2 are found in clusters around the world. HTLV-1 is found in PNG, Melanesia, Solomons, central Australia, central Africa, the Caribbean, Brazil, and southern Japan. PNG, Melanesia and central Australia have a unique subtype named ‘c’ [HTLV-1c]. The significance of this subtype on clinical outcomes is not clear.

HTLV-2 is found in the Americas. Certain subtypes of the virus predominate in different countries.

What diseases have been associated with HTLV1/2?

The diseases associated with HTLV include:

• Malignancy – Adult T cell leukemia/lymphoma (ATLL). This T cell associated malignancy occurs after 20-30 years of infection with HTLV-1 and has four different clinical presentations which display varying speed of onset: 1) acute, 2) lymphomatous, 3) chronic, and 4) smouldering. It is estimated that 2-4% of chronically infected HTLV-1 persons will develop ATLL. Survival is poor although treatment is still available in the form of chemotherapy.
• HAM (HTLV-1 associated myelopathy – also known as Tropical spastic paraparesis – [TSP]). This is a degeneration of the spinal cord that causes a spastic transverse myelitis involving predominantly the lower limbs and impaired bladder function. It is estimated that 0.25-3.7% of chronically infected HTLV-1 persons will develop this syndrome. Symptoms do not present until at least 30-40 years of HTLV-1 infection. The current hypothesis behind the mechanism of damage is that the neuronal and glial cells are destroyed as a ‘bystander effect’, whereby the infected close by CD4+ T cells are targeted by cytotoxic T cells for destruction and the toxic cellular contents and effect of cytotoxic T cells damages the surrounding neurons. This is yet to be conclusively proven. There are some treatments (all with little evidence that are used to help). These include corticosteroids, and Interferon alpha and beta. See attached article on HAM.
• Strongyloides – HTLV-1 has been associated with disseminated strongyloidiasis that reoccurs.
• Dermatitis – HTLV-1 associated infective dermatitis (HAID) is the most common presentation in children. It is characterised by chronic eczema like eruption with persistent Gram positive skin infections.
• Blood stream infection -. There are increased rates of blood stream infection in those infected with HTLV-1.
• Bronchiectasis – HTLV-1 has been shown to be associated with bronchiectasis

What are the most common methods of HTLV-1 spread in communities?

3 major routes for infection:

• mother-to-child transmission (mostly with breast-feeding)
• sexual transmission
• transfusion of cellular blood products infected with HTLV-1

What are the techniques for testing for HTLV1 and 2?

Methods of testing include screening for antibodies produced in defense of infection. This typically involves an enzyme immunoassay (EIA) which is then confirmed by a western blot (see references).

Pro-viral DNA can be detected in these cases but is often left only for research purposes.

References

1. Takao et al. Journal of Clinical Virology, Seroprevalence of human T-lymphotropic virus type 1 in Papua New Guinea and Irian Jaya measured using different Western blot criteria.  
2. Lab tests online HTLV 
3. Buxton et al. NRL, Presentation: HIV-1 western blot interpretation/analysis
4. McGill et al 2012.  HTLV-1-associated infective dermatitis: updates on the pathogenesis 

Image reference – http://plaza.ufl.edu/roxanna/HTLV%20projects.htm