Human T-cell lymphotropic virus (HTLV) types 1 and 2


Overview

Human T-cell lymphotropic virus types 1 and 2 (HTLV-1 and HTLV-2) are retroviruses found worldwide. Of the 2 viruses, HTLV-1 has been more often associated with human disease. It is the causative agent of a form of blood cancer (adult T-cell leukaemia or lymphoma, called ATL) and of a progressive disease of the nervous system (HTLV-1 associated myelopathy, or HAM, also known as tropical spastic paraparesis (TSP)).

Epidemiology

HTLV-1 infects at least 5 million to 10 million people worldwide, although information is unavailable for many countries, so this figure is likely to be an underestimate. The virus is endemic in:

  • Caribbean
  • South America
  • Romania
  • Iran
  • much of Africa
  • Japan
  • Melanesia
  • indigenous population of Australia

In England and Wales, an estimated 22,000 people are living with the virus, mainly those who have migrated from endemic countries, or their descendants.

Virology

HTLV-1 is an enveloped, single-stranded RNA virus of the family Retroviridae. The virus displays CD4 T-cell tropism and spread is by direct cell-to-cell contact. Viral RNA is not found in plasma. New infection is therefore usually the result of the transfer of infected lymphocytes rather than cell-free particles. After entering a cell, HTLV-1 RNA is reverse transcribed into DNA, which integrates into the host genome, where it is termed a provirus.

HTLV-1 is oncogenic (cancer-causing) and this is mediated through interaction between viral and host proteins, leading to T-cell proliferation and transformation. HAM/TSP is driven by the cellular immune response mounted against HTLV-1, which causes damage to the central nervous system.

Transmission

HTLV-1 is transmitted through many routes:

  • mother to child, especially through breastfeeding; also during pregnancy and giving birth
  • sex
  • injection drug use
  • blood transfusions and organ transplantation
  • occupational exposure
  • certain cultural and religious practices (such as flagellation)

Due to the risk of transmission through blood transfusion, new blood donors and returning donors of unknown status are tested for HTLV in the UK; organ donors are also tested.

Clinical features

About 5% to 10% of people with HTLV-1 will develop a recognised associated clinical condition. In addition, mortality is higher in people with HTLV-1 who do not have a recognised condition, but the reason for this is as yet unknown.

Adult T-cell leukaemia or lymphoma (ATL)

Clinical features of ATL include:

  • generalised swelling of the lymph nodes
  • enlarged liver and spleen
  • immunosuppression
  • high blood calcium levels
  • bone and skin lesions

Of the 4 types of ATL, the acute and lymphoma forms are the most aggressive, with a median survival of less than one year.

HTLV-1 associated myelopathy (HAM) or tropical spastic paraparesis (TSP)

HAM, also known as TSP, is characterised by progressive weakness and spasticity of both legs. The prognosis is variable but a substantial proportion of individuals will not be able to walk unaided 10 years after onset, with 50% eventually becoming wheelchair dependent.

Other clinical conditions

Other clinical conditions associated with HTLV-1 infection include:

  • uveitis (inflammation of the middle part of the eye)
  • infective dermatitis (eczema-like skin rash)
  • disseminated strongyloidiasis (a parasitic helminth worm)
  • damage to the peripheral nerves
  • bronchiectasis (inflammation and widening of the airways with build-up of mucous)
  • inflammation of the joints

Diagnosis

The diagnosis of HTLV infection is usually made by testing for HTLV antibodies in blood samples using enzyme-linked immunoassay. Reactive samples are confirmed by a Western blot or line assay, which also type the infection. Where serology is inconclusive, PCR for proviral DNA is performed. For this, whole blood is required to allow extraction of DNA from lymphocytes.

Treatment and prevention

Treatment is not indicated for people living with HTLV-1 who do not have a clinical condition.

However, all individuals are recommended to attend specialist services regularly to:

  • promptly identify the onset of any symptoms
  • access clinical trials in those cases where therapy is required
  • seek advice on how to prevent transmission to others, such as through the avoidance of breastfeeding, not donating blood and use of condoms when having sex

Screening for associated diseases, such as strongyloidiasis, is offered to people who are newly diagnosed.

Although anti-HIV drugs, which have activity against the HTLV-1 reverse transcriptase (RT) and integrase enzymes have been tested in limited clinical trials, HTLV-1 proviral DNA level is not reduced. Anti-HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTI) have no anti-HTLV activity. RT and integrase inhibitors may have a role in prevention of HTLV infection but further studies are required to confirm this (see PEP section).

ATL can be treated with chemotherapy, monoclonal antibodies or bone marrow transplant, but treatment outcomes are often poor. Zidovudine and interferon-alpha is the recommended first-line treatment for leukaemic forms of ATL. Prophylaxis against opportunistic infections is important. Corticosteroids and steroid-sparing anti-inflammatory agents may slow progression in some patients with HAM/TSP; a monoclonal antibody is also being tested in clinical trials. International recommendations have recently been published for ATL and HAM/TSP management.

Better treatments are urgently needed for conditions caused by HTLV and general recommendations beyond the management of HAM/TSP and ATL cannot yet be made.

Post exposure prophylaxis (PEP)

Few cases of occupational exposure have been described in the literature and no instances where prophylaxis has been given after an HTLV exposure in humans. Significant exposures include exposure to cellular fluid (such as whole blood) of an HTLV-infected patient through needlestick injury, particularly where the proviral DNA level is high.

In vitro data show that raltegravir, a drug that prevents integration of HIV DNA into the host genome, and certain HIV-1 nucleoside analogue reverse transcriptase inhibitors also have activity against HTLV-1. In the absence of clinical data, some specialists recommend that individuals who have sustained a significant occupational exposure to HTLV-1 should receive post exposure prophylaxis with raltegravir, zidovudine and lamivudine for 6 weeks.

HTLV-2

HTLV-2 has mainly been detected in indigenous Americans and people from Western Africa; it is less common in the UK than HTLV-1. Transmission is through the same routes as HTLV-1, with a particularly strong association with injecting drug use in some groups. However, there are no recent data on the prevalence of HTLV-2 in people who inject drugs in the UK. HTLV-2 is less frequently associated with disease than HTLV-1 and, where disease does occur, it is generally milder. However, there is currently little information available about the role of HTLV-2 in disease.

Surveillance

PHE coordinates national HTLV surveillance activities. Laboratory reports of new diagnoses are received from the PHE Viral Reference Department (VRD), at Colindale, which confirms all HTLV diagnoses in England and Wales. Clinical data on new diagnoses are received on an annual basis from the 4 centres providing specialist HTLV-1 care below:

  • St Mary’s Hospital (Imperial College Healthcare NHS Trust)
  • Queen Elizabeth Hospital Birmingham (University Hospitals Birmingham NHS Trust)
  • North Manchester General Hospital (Pennine Acute Hospitals NHS Trust)
  • Monkgate Health Centre (York Teaching Hospital NHS Foundation Trust)

HTLV diagnoses data from the NHSBT, which monitors HTLV infection in blood donors, are also incorporated into the surveillance dataset.



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