Human T-cell Leukemia Virus

Genome and Structure:

    The genetic structure of HTLV is similar, but distinct from other retroviruses.  HTLV contains the normal gag, pol, and env genes that other retroviruses possess.  However, there is an additional region found on the 3' end of the genome possessing the genes tax and rex.  These two genes are essential for viral replication.

There is a nontranslated region of about 600 nucleotides in HTLV.  While some studies show that there might be some proteins encoded in this region, much of the region can be removed with no deleterious effects on replication.

Genetic Variation:  HTLV-I and HTLV-II have approximately a 65% similarity in nucleotide sequences. Homology between the sequences is highest in the tax and rex genes, and lowest in the LTR and nontranslated region.  HTLV envelope proteins appear unable to sustain many mutations without becoming non-functional.


Modes of Transmission:

HTLV-1 enters the body primarily through infected CD4+ lymphocytes. HTLV-II is found predominantly in in CD8+ cells.  The cellular receptor for HTLV is unknown.  It is likely that HTLV can penetrate and infect many different cell types, however productive infection is observed in only a few cell types.  HTLV establishes a lifelong persistent infection which usually remains subclinical, but occasionally produces disease after an incubation period ranging from ten to forty years.  Clinical manifestations vary.

Oncogenic Potential:

Both HTLV I and II will immortalize primary human peripheral blood T cells in vitro.  Patients with Adult T-cell Leukemia usually have CD4+ tumors, however occasional CD8+ tumors have been reported.  The molecular mechanisms that HTLV uses to transform T cells is unknown.  HTLV carries no viral oncogene.  The oncogenic potential of the virus is linked to the regulatory gene tax, which transactivates transcription of proviral LTR, cellular oncogenes, and the cellular gene encoding the growth factor inerleukin-2 receptor.  This can cause a cascade of events that has the potential to lead to cancer by inducing autocrine stimulation of T-cell proliferation.


Symptomatology and Outcome:

Most HTLV infections remain asymptotic.  However, there is a 1-4% risk of disease development, usually between the ages of 30-50 after an incubation period of 10-40 years.
The two most distinct clinical manifestations caused by HTLV-1  are Adult T-cell Leukemia/Lymphoma (ATL) and Tropical Spastic Paraparesis (TSP).  Less is known about HTLV-2, but is common among intravenous drug users and linked to a form of atypical hairy cell leukemia.

Adult T-cell Leukemia/Lymphoma:

Tropical Spastic Paraparesis: Other Diseases Possibly Associated with HTLV-1:
    T-cell non-Hodgkin's lymphoma, T-prolymphocytic leukemia, Sezary's syndrome,
    mycosis fungoides, small cell carcinoma, and large granular lymphyocytic leukemia

Diseases Associated with HTLV-II:
    No absolute role of HTLV-II has been determined at this point, however there has been a connection with atypical hairy-cell leukemia.  Atypical hairy-cell leukemia is used to distinguish the disease from T and B-cell hairy cell leukemias which are not connected with viral infections.  Other diseases with possible connections to HTLV-II are very similar to the ones caused by HTLV-1 and include spontaneous lymphocyte proliferation, mycosis fungoides, large granular lymphocyte leukemia, and neurological complications similar to TSP.



Mapping the geographic distribution of HTLV-I and HTLV-II  has been difficult because conventional serologic approaches cannot distinguish between HTLV-I and HTLV-II. Approximately 10-20 million people around the world are estimated to be infected with HTLV-I.  There has been a tendency for the geographic distribution of HTLV-1 to center around the tropics.   Areas with the highest prevalence of HTLV-I infections include southern Japan, the Caribbean, equatorial Africa, parts of South America, eastern Siberia, and the Pacific islands.  HTLV-II predominates in Native American populations and among intravenous drug users.


Prevention and Management:


    Adult T-cell Leukemia is highly malignant and during subacute or acute ATL, survival is measured in only a few months.  Treatment is only reserved for those with subacute or acute ATL, because other infected individuals only have a 1% chance to progress to a symptomatic state.  Standard chemotherapy does not prove to be very effective for ATL.  Currently , no drugs have shown to be valuable treatment agents.  There have been studies showing variable effectiveness for drugs such as deoxycoformycin and ubenimex.  Beta and gamma interferon along with anti-Tac antibody have been shown to induce remissions in a few ATL patients.
    Attempts to treat Tropical Spastic Paraparesis have included oral corticosteroids, but variable efficacy has been shown in clinical studies.  High dose intravenous gamma globulin has shown beneficial effects, but these effects are only short term.  Significant progress cannot be made for the treatment of TSP until more is understood about the pathogenesis of the virus.

Vaccine development:
    While there is no present licensed vaccine, there are many factors which make a vaccine against HTLV-1 feasible.  The virus displays relatively low antigenic variability, natural immunity does occur in humans, and experimental vaccination using envelope antigens has been shown to be successful in animal models.