Human T-cell Lymphotropic Viruses (HTLV)


In 1980, it became possible to propagate human T lymphocytes with the help of IL-2. Long term cultivation of lymphocytes from patients with T cell leukaemias yielded retrovirus with C-type morphology. HTLV-I and II share most properties such as density, morphology, a 70S RNA, reverse transcriptase and structural proteins with all other replication-competent C-type retrovirus. The major HTLV core protein p24 was shown to be serologically distinct from the core proteins of all previously described viruses. HTLV-I and HTLV-II are often dubbed the "forgotten human retroviruses" in the wake of the massive and unprecedented attention and resources dedicated to HIV. It should not be forgotten though that the discovery of HTLC-I paved the way for the discovery of HIV.

A. Properties

Belong to the oncornavirus subfamily of retroviruses
ssRNA enveloped virus
Two copies of the RNA genome with 3 major genes:
gag (structural proteins, pol (reverse transcripatse), and env (envelope glycoproteins)
Both HTLV-I and HTLV-II are tropic for OKT4+ T-helper lymphocytes but other cells can be infected.
In contrast to HIV, the cellular receptor is not known.
Both HTLV-I and HTLV-II can transform suitable target cells in vitro.
Despite the ability to transform, both viruses do not possess a specific oncogene

B. Epidemiology

Seroepidemiological studies reveal that HTLV-I infection occurs in clusters in certain geographic locations around the world. It is endemic in Southern Japan (15-30%), Caribbean (3-6%), Papua New Guinea and some parts of Africa. HTLV-I appears to be transmitted sexually and through blood. Vertical transmission is thought to play an important role in the maintenance of virus in areas of high endemicity. Transmission through breast milk is implicated as a major route for the maintenance of infection in high prevalence areas. Transmission may also occur via the sexual route. Seroprevalence of HTLV-I increases with age and is twice as high in females than males. In Southern Japan, HTLV-I seroprevalence in persons over 80 years was 50% in females and 30% in males. This gender difference usually emerges after 30 years and probably reflects more efficient transmission from males to females during sexually active years. HTLV- II infection is particularly common in IV drug abusers, and has been found in clusters among certain South American Indians. Reports have documented kidney, liver, and lung transplant transmission of HTLV-1

Six different HTLV-1 subclasses exist, and each subtype is endemic to a particular region.

Subtype A (cosmopolitan subtype) - Japan
Subtypes B, D, and F - Central Africa
Subtype C - Melanesia
Subtype E - South and Central Africa

HTLV-2 is classified into 4 molecular subtypes. Each has a characteristic geographic association.

Subtypes A and B - Present throughout Western Hemisphere and Europe; sporadic distribution in Asia and Africa
Subtype C - Kayapo indigenous people of the Amazon and urban Brazilian populations
Subtype D - Discovered in an African pygmy tribe

C. Disease Associations

HTLV-I is associated with at least 2 kinds of disease manifestation; adult T-cell leukaemia and tropical spastic paraparesis.

  1. Adult T-cell leukaemia - the evidence implicating HTLV-I as the aetiological agent of ATL includes the association of ATL with HTLV-I antibodies, the isolation of the virus, the finding of monoclonal integrated proviral sequences in leukaemic cells of patients with ATL, and epidemiological data. ATL, in the majority of cases, is a rapidly progressive fatal disease and affects 1 in 500 of persons infected by HTLV-I. It is characterized by diffuse lymph node infiltration, hypercalcaemia, leukaemia, skin infiltrates, and a positive HTLV-I antibody test. An incubation period of 15 to 20 years have been suggested for the development of ATL. ATL has been reported to develop in 2%-4% of individuals with HTLV-1 infection.

  2. Tropical Spastic Paraparesis - the association of HTLV-I with TSP was discovered in 1985 while screening blood donors for HTLV-I antibodies in Martinique, West Indies. More than 75% of patients with TSP were found to have antibodies against HTLV-I and the association is further supported by the isolation of HTLV-I from the blood and CSF of patients with TSP. A chronic neurological disorder identical with TSP was found subsequently in other regions endemic for HTLV-I such as Africa and Japan, where TSP was named HTLV-I associated myelopathy. Clinically, TSP resembles multiple sclerosis, but lacks the intracranial nerve signs and remissions characteristic of MS. Initial symptoms are bilateral weakness and stiffness of the lower extremities. The course is slowly progressive, usually with bladder involvement, but shows considerable variations. HAM/TSP has been reported to develop in 1%-2% of individuals with HTLV-1 infection

  3. Other Associations  - HTLV-I infection has been associated with a large variety of clinical syndromes, of which there is strong evidence in the case of HTLV-I associated infective dematitis and HTLV-I associated uvetis. It is likely that the spectrum of disease associations with increase with time.

D. Laboratory_Diagnosis

  1. Serology - Laboratory diagnosis rests mainly on the detection of antibodies against using screening EIAs. A passive particle agglutination assay (Serodia) is also available and is widely used in Japan for the screening of blood donations. Current EIAs cannot distinguish between HTLV-I and HTLV-II. However, a commercial Western blot using recombinant HTLV antigens are available which can distinguish between HTLV-I and HTLV-II. There appears to be some correlation between the titre of anti-HTLV-I antibody and the likelihood of developing ATL and TSP in HTVL-I carriers.

  2. Detection of proviral DNA - PCR can also be used to detect HTLV from peripheral blood mononuclear cells and can distinguish between HTLV-1 and HTLV-II. There is also interest in quantitative PCR assays to quantify viral load since, as in the case of antibody titre, there appears to be correlation of high viral loads with the likelihood of developing ATL and TSP in HTLV-I carriers.

E. Management

There is a possibility that some of the agents currently in use against HIV, especially the nucleoside analogue inhibitors, may work against HTLV-1. However, since ATL and TSP present years following infection, there appears little justification in using antiviral therapy in healthy carriers. A combination of interferon-alpha and zidovudine had been reported to be effective in treating ATL patients. A combination of zidovudine, danazol, and Vitamin C in providing temporary relief for TSP patients.

F. Prevention

Screening of blood donations for HTLV-I is now routinely carried out in high prevalence areas such as Japan. However, there is a trend towards screening in low prevalence areas as well e.g. USA and France. In other low prevalence areas, screening is only carried out on donors who originate from high prevalence areas e.g. Japan and the Carribean. In Japan, antenatal screening for HTLV-1 antibody is carried out for pregnant wowen. Those who are positive are advised not to breastfeed their infants. Research is being carried out on the development of a vaccine against HTLV-I.