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.
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.
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
gene and the 5' part of the pol gene; synthesis of the protease
is accomplished by ribosomal frameshifting.
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.
Encodes a 61-69 kd glycoprotein which is cleaved into a 46 kd surface glycoprotein
and a 21 kd transmembrane protein.
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.
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
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.
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.
occurs as a mother passes on the virus to her baby during delivery or through
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:
Tropical Spastic Paraparesis:
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.
lead to a variety of opportunistic infections.
Death usually occurs in
a year following acute ATL.
Other Diseases Possibly
Associated with HTLV-1:
Also known as HTLV-1 Associated
Carriers of the HTLV-I
virus have less than a 1% chance of developing TSP.
Most common in 20-50 year
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
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
T-cell non-Hodgkin's lymphoma, T-prolymphocytic leukemia, Sezary's syndrome,
mycosis fungoides, small cell carcinoma, and large granular lymphyocytic
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.
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
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