Human T-cell Leukemia Virus

    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.

• gag:  Translated as a polyprotein precursor and cleaved into three gag polypeptides:  a 19 kd matrix protein, a 24 kd capsid protein, and a 15 kd nucleocapsid protein.   Shown to be important in the assembly and budding of virus particles.  The protease is encoded in the 3' part of the gag gene and the 5' part of the pol gene; synthesis of the protease is accomplished by ribosomal frameshifting.
• pol:  Encodes an amino acid product, but a frameshifting event is necessary for full expression of the pol gene.  The 5' end of the gene encodes reverse transcriptase and further downstream, the gene encodes integrase and RNAse H.   As mentioned above, the protease is encoded in the 5' part of the pol gene.
• env:  Encodes a 61-69 kd glycoprotein which is cleaved into a 46 kd surface glycoprotein and a 21 kd transmembrane protein.
• tax:  Encodes for a protein responsible for transcriptional activation of the long terminal repeat (LTR).  The protein product is located primarily in the nuclear matrix of infected cells.   The tax protein is a trans-acting transcriptional activator and it is responsible for the increased rate of transcription from the promoter in the 5' LTR of the provirus genome.  Tax has been shown to affect a great number of different cellular transcription factors, and can play a large role in the control of cellular transcription and immune activation of lymphoid cells.  Beleived to initiate the leukemogenic process.
• rex:  Encodes two proteins, the larger of which is involved in the control of HTLV gene expression.  This Rex protein is necessary for expression of structural proteins and acts at a post transcription level to regulate viral gene expression.  This protein regulates splicing of RNA transcripts and has a negative effect on its own production and that of Tax, which could lead to decreased expression of all the viral genes and might reestablish latency.  The function of the smaller protein is unknown.  Rex proteins are phosphorylated and are localized in the nucleus of infected cells.

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:

• Parenteral transmission takes place via contaminated blood or tissue such as through transplants or shared intravenous drug needles.
• Sexual transmission places the receptive partner at the greatest risk.  Having multiple sexual partners is considered a very high risk behavior.
• Vertical transmission occurs as a mother passes on the virus to her baby during delivery or through breast milk

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.

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:

• Characterized as an acute aggressive leukemia of mature CD4+ T lymphocytes.
• An individual infected with HTLV-1 has about a 1% chance of developing a tumor.
• There are five stages of ATL:   (1) asymptomatic carrier stage, (2) preleukemic state, (3) chronic/smoldering ATL, (4) lymphoma type, and (5) acute ATL.
• Most HTLV-1 infected individuals are asymptomatic carriers of the virus.
• The preleukemic state and chronic/smoldering ATL stages represent transitional states in the development of malignancies evident in acute ATL.
• Malignant cells are pleomorphic with large distorted nuclei.
• Immunosuppression can lead to a variety of opportunistic infections.
• Death usually occurs in a year following acute ATL.

• Also known as HTLV-1 Associated Myelopathy
• Carriers of the HTLV-I virus have less than a 1% chance of developing TSP.
• Most common in 20-50 year old women
• This is a neurological disease where the virus infects the central nervous system in addition to the blood.
• Characterized by progressive demyelination of the long motor neuron tracts of the spinal cord
• Clinical manifestations start with lumbar back pain which radiates down the legs, leading to dysethesia, urinary frequency or retention, and sometimes mild sensory loss.
• Other symptoms include weakness and spasticity of the extremities, hyperreflexia

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.

Treatment:
    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.