What is HTLV-I?

HTLV-I is the short name of the "Human T-Lymphotropic Virus type I". It is called this because it
infects a type of white blood cell called a T-lymphocyte. HTLV-I is a virus. A virus is a minute organism that
usually can only be seen when magnified many thousand times by an electron microscope. Viruses do not
have their own metabolism (life-support system) and can only make all their component parts (ie. genetic
code, enzymes, sugars and proteins) by infecting living cell. Once formed viruses are released from the
infected cell. To replicate again they must find a new cell to infect.

Worldwide distribution of HTLV-I infection

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Who is likely to be infected by HTLV-I?

HTLV-I is a very old virus, which appears to have infected and moved with mankind for hundreds, perhaps
thousands of years. It is thought to have migrated during ancient times with native American Indians in
North and South America, with Australian aborigines and the Melanesian people of the South West Pacific,
and to Japan. During the last few centuries it has migrated from Africa to the Caribbean and again to North
and South America. In some areas more than 1% of the population carry the virus. The same rates of
infection are seen in populations wherever they migrate. In Europe HTLV-I is mainly found among people
who have originated from these endemic areas.

How would I know if I am infected

Most people who are infected with HTLV-I are completely unaware of the infection because they are
perfectly well. As they have no symptoms or signs of the infection this is known as asymptomatic carriage.
We have estimated that in the UK 22,000 people are infected with HTLV-I but most are asymptomatic
carriers and less than 1000 are aware of the infection.

You are a blood donor and have been screened for HTLV-I and other infections.

A family member or your partner is infected with HTLV-I.

You have developed symptoms which resemble those the virus can cause.

The presence of HTLV-I infection can be detected by a blood test. Soon after infection with HTLV-I the body
will respond by producing antibodies to fight the infection. HTLV-I antibodies, which are produced only in
response to HTLV-I infection and not to any other infection, can easily be detected in the laboratory but only
if the specific test is done. HTLV-I infection does not show up in routine blood tests such as those requested
by your family doctor or in routine hospital tests.
Because HTLV-I causes a lifelong infection the presence of these antibodies is proof of infection. The
absence of HTLV-I antibodies excludes HTLV-I infection unless the infection has only just occurred and the
test was done before the body has had time to respond to the infection. If a recent infection is suspected the
antibody test should be repeated three months later.

How does HTLV-I infection occur

HTLV-I can be transmitted from person to person in four ways:

From an infected mother to her baby. Up to 1:4 children born to mothers with HTLV-I infection will
become infected. However most infections occur through breast-feeding and if this is avoided less
than 1 in 20 babies will become infected. The risk of infection through breast-feeding increases with
the duration of breast-feeding and may be low during the first three months.

HTLV-I infection is not routinely tested for in the UK ante-natal clinics so if you are pregnant and
think you may be a carrier, you need to speak to your doctor or midwife.

Between sexual partners through unprotected (no condom) intercourse. The risk of transmission
from an infected man is greater than from an infected woman. The best information indicates that in
a steady relationship lasting 5 years there is a 7% chance of transmission. Since the use of
condoms protects against many other, more infectious, infections we recommend the use of
condoms, unless a couple are trying to have a baby.

Through transfusion of blood from an HTLV-I infected donor. The risk may be as high as 85% but
depends on how the blood is handled and stored. Persons with HTLV-I infection should not donate
blood, organs or sperm and should not carry an organ donor card. All blood donations in the UK are
screened for HTLV-I infection.

Through the sharing or re-use of needles and syringes to inject drugs. The use of disposable
equipment for injections prevents transmission.

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Does HTLV-I cause any disease?

The vast majority of persons infected with HTLV-I DO NOT DEVELOP ANY DISEASE due to HTLV-I. The virus
appears to remain in the body throughout life without causing any harm at all. A small minority, about 1
person in 20, will develop disease due to HTLV-I but this usually occurs only after several decades of
infection. There are two main types of disease caused by HTLV-I:
Adult T-cell Leukaemia/Lymphoma (ATLL). This is a rare form of cancer of the blood seen in less than
20 patients per year in the UK. It is usually treated with anti-cancer drugs but recent progress has shown
that starting with anti-cancer treatment and then switching to anti-viral treatment is better. Bone marrow
transplantation should be considered for patients in remission with ATLL.
HTLV-I-associated myelopathy (HAM). This is an inflammation of nerves in the spinal cord that causes
stiffness and weakness of the legs, backache, a 'weak' bladder and constipation. Not all of these symptoms
may be present, especially at the beginning. The disease often starts very slowly and the symptoms may be
attributed to arthritis or getting old. Different medicines are available to treat the various symptoms:
stiffness, pain, 'weak' bladder etc. The use of anti-inflammatory medications is now under investigation. In
the UK about 10 persons are diagnosed with HAM each year.
Other HTLV-I-associated diseases. HTLV-I can also cause inflammation of the eye (uveitis), joints
(arthritis), muscles (myositis), lung (alveolitis) and skin (dermatitis). These conditions are even less
common than ATLL and HAM and the skin condition is usually only seen in tropical climates.
HTLV-I and other infections
Strongyloidiasis: A warm infection acquired in the tropics can, after lying dormant for years, cause a
serious illness in HTLV-I carriers. Although rare in the UK, all HTLV-I carriers who have lived in the tropics
should be screened for Strongyloidis.

Can HTLV-I infection be treated?

At present there is no treatment to cure (eradicate) the infection. Since 95% of all infected persons go
through life without developing any HTLV-I-associated diseases any such treatment would have to be not
only effective but also very safe.

Is everyone infected with HTLV-I at equal risk of developing an HTLV-I-associated

disease?
ATLL is unlikely to develop following infection acquired in adult-life. This means that avoiding infection of
babies by avoidance of breast-feeding is very important for the prevention of ATLL in the next generation.
HAM seems to be less common among Japanese with HTLV-I infection than among other populations and
evidence is emerging that the immune system is important in controlling infection. HTLV-I asymptomatic
carriers with less virus in the blood are less likely to develop HAM.

The National Centre for Human Retrovirology

What is HTLV-II?
Who is infected with HTLV-II?
How does HTLV-II infection occur and how can infection be prevented?
How would I know if I am infected?
What happens after somebody has been infected with HTLV-II?
Does HTLV-II cause any disease?
Can HTLV-II infection be treated?
What is the difference between HTLV-I and HTLV-II?

What is HTLV-II?
HTLV-II stands for "Human T-Lymphotropic Virus type II". This virus infects a type of
white blood cell called T-lymphocytes which are important in fighting
infections. A virus is a tiny organism that cannot be seen without
magnification. Viruses do not have a metabolism (life support) of their own
and can only live and multiply within a living cell. Once a new virus is formed
it is released from that cell and must find a new cell to infect.

Who is infected with HTLV-II?

HTLV-II infection has been found in Western Africa and may have originated
there. It is thought to have migrated during ancient times with native
American Indians to North and South America.
In modern times HTLV-II infection has spread among injecting drug users
(IDUs) particularly in America, South Vietnam and Europe. In Europe the
highest rates of HTLV-II are found amongst injecting drug users in Eire, Spain,
Italy and Scandinavia.
The exact number of people infected in the UK is not known but is much less
then the number infected with HTLV-I. For example, only 1 in 100,000 blood
donors in the UK was found to carry HTLV-II compared with 1 donor in 20,000
for HTLV-I. How these people have become infected with HTLV-II is often
uncertain as on many occasions no risk factors are identified.
Top

How does HTLV-II infection occur and how can infection

be prevented?
HTLV-II infection is transmitted from person to person by one of four possible
routes:

From an infected mother to her baby. Most infections occur through

breastfeeding. Research from Brazil and Argentina suggests that
around 30% of breastfed infants become infected. If a mother is
infected she should avoid breastfeeding and use formula feeds only.
A few infections occur either before delivery or during labour.

HTLV-II infection is not routinely tested for in the UK ante-natal

clinics so if you are pregnant and think you may be a carrier, you
need to speak to your doctor or midwife.

Between sexual partners through unprotected (no condoms)

intercourse. The use of condoms, which protect against other
infections, is likely to prevent most sexual transmission of HTLV-II.

Through transfusion of blood from a HTLV-II infected donor. Only

blood products that contain cells, such as whole blood, red blood cells
and platelets contain the virus. Plasma is not infectious. Persons with
HTLV-II infection should not donate blood, organs or sperm and
should not carry an organ donor card. HTLV-II infections are detected
by the screening tests used by the National Blood Service in the UK
to identify HTLV-I infection in blood.

By the sharing or re-use of needles and syringes to inject drugs. The

use of disposable equipment for injections prevents transmission.

How would I know if I am infected?

Most people who are infected with HTLV-II are unaware of this infection. You
may have been tested or may wish to be tested because:

You are a blood donor and have been screened for HTLV-II and other
infections.

A family member or your partner is infected with HTLV-II.

You have developed symptoms which resemble those the virus can
cause.

You have been found to have another viral infection with similar
routes of transmission e.g. Hepatitis C virus.

The only way to find out if you are infected is to perform a special blood test
which detects HTLV-II antibodies. The presence of HTLV antibodies is proof of
infection. The test may show negative if infection has only just occurred. If
recent infection is suspected the antibody test should be repeated three
months later.

What happens after somebody has been infected with

HTLV-II?

Cells responsible for the body's defence against infections will recognise the
virus as foreign to the body and try to clear the infection. However the body is
unable to clear the HTLV-II virus completely. A balance between the virus and
the body will be reached, where virus reproduction continues but is controlled
by the immune system. This state is called asymptomatic carriage because the
infection does not cause disease. In a very few cases, however, symptoms will
develop.
Top

Does HTLV-II cause any disease?

The vast majority of persons infected with HTLV-II, greater than 99%, do not
develop any disease due to HTLV-II. The virus appears to remain in the body
throughout life without causing any harm. HTLV-II disease associations are
less well established than those of HTLV-I but HTLV-II has been associated
with myelopathy - an inflammation of nerves in the spinal cord - which leads
to stiffness and weakness of the legs, backache, a "weak" bladder and
constipation. The damage appears to be caused by chemicals released from
immune cells fighting the infection which inadvertently harm the nerves. A
study of HTLV-II infected carriers in North America shows that people infected
with HTLV-II have a small increased risk of bacterial infections, particularly of
the chest and bladder.

Can HTLV-II infection be treated?

Treatment is not required for asymptomatic patients who are usually followed
up in the clinic annually. The various symptoms of myelopathy are treated as
required and drugs which may reduce the amount of the virus in the blood or
reduce inflammation can also be tried. At present there is no cure for the
infection.

What is the difference between HTLV-I and HTLV-II?

HTLV-I and HTLV-II are closely related viruses but tend to infect different
populations and are associated with different diseases and different rates of
disease. Although both can cause amyelopathy, an inflammation of the spinal
cord, this is much more common with HTLV-I. HTLV-I, but not HTLV-II, can
also cause leukaemia - a blood cancer.
The screening tests detect both HTLV-I and HTLV-II infections. Further tests
are used to distinguish the two viruses.

Background
Human T-cell lymphotropic virus (HTLV) was the first human retrovirus discovered. HTLV belongs to the
Retroviridae family in the genus Deltaretrovirus. Retroviruses are RNA viruses that use an enzyme called
reverse transcriptase to produce DNA from RNA. The DNA is subsequently incorporated into the hosts
genome. HTLV predominantly affects T lymphocytes.
Prior to 1979, the isolation of retroviruses was possible only in nonhuman primates; in fact, it was
believed that human retroviruses did not exist. In 2005 inRetrovirology, Gallo reflected about earlier
concepts that supported this belief. First, if human retroviruses did in fact exist, then why had they not yet
been discovered? Second, the virus was easily detected in animals, and therefore should have also been
easily detectable in humans. Third, technical difficulties hampered efforts to grow primary human cells in
the laboratory. Finally, it was shown that the human complement lyses animal retroviruses in vitro,
suggesting erroneously that humans were intrinsically protected from these viruses.[1]
In 1979, T-cell lymphotropic virus was isolated in a patient with cutaneous T-cell lymphoma.[2] This led to
the discovery of the first HTLV and marked the beginning of the human retrovirus era. Two years later,
HTLV-2 was documented in a patient who had been diagnosed with hairy cell leukemia,[3] although
subsequent studies showed no affiliation between the two processes.
In 1983, the third and most important retrovirus was discovered. At the time of its discovery, this virus was
classified in the HTLV genus. However, upon further research, it was reclassified into the Lentivirus

genus and given the name human immunodeficiency virus (HIV). In 2005, two novel viruses, HTLV-3 and
HTLV-4, were discovered. Little is known about these viruses, as only a few cases have been reported.
Now, 30 years later after the initial discovery, 4 HTLVs are well established. HTLV-1 and HTLV-2 are both
involved in actively spreading epidemics, affecting 15-20 million people worldwide.[4] In the United States,
the overall prevalence is 22 per 100,000 population, with HTLV-2 more common than HTLV-1. Data
collection performed from 2000-2009 among US blood donors has shown a general decline since the
1990s.[5]
HTLV-1 is the more clinically significant of the two, as it has been proven to be the etiologic agent of
multiple disorders. At least 500,000 of the individuals infected with HTLV-1 eventually develop an often
rapidly fatal leukemia, while others will develop a debilitative myelopathy, and yet others will experience
uveitis, infectious dermatitis, or another inflammatory disorder. HTLV-2 is associated with milder
neurologic disorders and chronic pulmonary infections. The novel HTLV-3 and HTLV-4 have been
isolated only in a few cases; no specific illnesses have yet been associated with these viruses.

Pathophysiology
HTLVs are intracellular proviruses that pass through formation of a "virological synapse", allowing the
viral genome to be passed from one cell to another. Once infection has occurred, little replication takes
place. Infection affects the expression of T-lymphocyte gene expression, leading to increased proliferation
of affected T lymphocytes. HTLV primarily affects T lymphocytes: specifically, HTLV-1 predominantly
affects CD4 lymphocytes, while HTLV-2 predominantly affects CD8 lymphocytes. In vitro, HTLV-1 is also
capable of infecting other cell types, possibly accounting for the diverse pathogenesis of HTLV-1.
Recently, GLUT-1, a ubiquitous glucose transporter, has been identified as a receptor for HTLV-1[6] ; this
may explain its ability to infect various cell types.
Acute HTLV infection is rarely seen or diagnosed, as most infections are latent and asymptomatic.
Infection might be diagnosed after an attempted blood donation or through workup of a disease caused
by the virus. For example, HTLV-1 is associated primarily with two diseases, adult T-cell leukemia (ATL)
and HTLV-1associated myelopathy/tropical spastic paraparesis (HAM/TSP).
HTLV-1 and HTLV-2 have similar transmission patterns, although the transmission efficiency of HTLV-2 is
uncertain because of a lack of unbiased data gathering. Both can be transmitted via breast milk, sexual
contact, and intravenous drug use, and both can be introduced directly into the vascular system. HTLV-3
and HTLV-4 seem to be transmitted through direct human contact with primates (eg, through hunting,
butchering, keeping them as pets), but data are lacking.[7]
On the molecular level, as with all retroviruses, HTLV has a gag-pol-env motif with flanking long terminal
repeat sequences. Unique to the Deltraviruses, however, it includes a fourth sequence named Px, which
participates in open-readingframe transcription, in turn encoding for regulatory proteins Tax, Rex, p12,
p13, and p30. All these proteins are important for the infectivity of cells, as well as in stimulating
replication. In ATL, the main pathogenic protein, Tax, leads to leukogenesis and immortalization of T
lymphocytes in vitro.[8] This is achieved by stimulation of interleukin-15 (IL-15) and interleukin-2 (IL-2), in
turn leading to T-cell growth and transformation. Research on this subject is ongoing, and the expression
of this gene is not always found in ATL cells.[9] Furthermore, Tax is inherent to both HTLV-1 and HTLV-2,
although HTLV-1 is more pathogenic.[10, 11]
Recently, the HTLV-1 basic zipper factor gene (HBZ) has been found to be consistently expressed in ATL
cells, suggesting a role in cellular transformation and leukemogenesis. This might correlate with the
increased pathogenesis of HTLV-1.[12] The expression of the HBZ gene also correlates with the provirus
load of HTLV-1.

Epidemiology
Because of the low replicating nature of HTLV, the virus develops little genetic sequence
variation.[4] Therefore, most epidemiologic data are based on serologic studies rather than on molecular
typing. Variations exist in the env gene for each HTLV; they define the HTLV subtypes. The distribution of
HTLV-1 and HTLV-2 subtypes is quite distinct and can probably be explained by differing evolutionary
trends.[4] HTLV-1 subtypes are associated with specific regions of the globe, while HTLV-2 subtypes are
related to highly specific subpopulations (eg, Brazilian Indians) and behaviors such as injection drug use.

Transmission of HTLV-1 and HTLV-2

Breastfeeding
HTLV-infected T cells in breast milk pass from mother to child. The risk of HTLV-1 transmission reaches
20% and is affected by the duration of breastfeeding, the proviral load, and the quantity of maternal
antibodies. Intrauterine infection is less common, about 5%.[13, 14, 15]
For HTLV-2, the quantitative risk remains uncertain for both breastfeeding and intrauterine transmission.

Sexual: Increased exposure and increased proviral load increase the risk of sexual transmission of both
HTLV-1 and HTLV-2.[16]
Transfusion: The risk of seroconversion due to contaminated blood transfusion has been reported to be
40%-60% and increases in immunosuppressed recipients.[17]
Transplant: Reports have documented kidney, liver, and lung transplant transmission of HTLV-1.[18]
Intravenous drug use: This mode of transmission is mostly linked to HTLV-2. The prevalence of HTLV-2
infection in North American injection drug users ranges from 8%-17%.[19]

HTLV-1
Six different HTLV-1 subclasses exist, and each subtype is endemic to a particular region. [4] . HTLV-1
clustering occurs, as evidenced by a high prevalence in southwestern Japan despite a low prevalence in
neighboring regions (eg, Korea, China, eastern Russia), although the cause of this is unknown. [20]

Subtype A (cosmopolitan subtype) - Japan

Subtypes B, D, and F - Central Africa
Subtype C - Melanesia
Subtype E - South and Central Africa
HTLV-1 is associated with the below diseases. Note that ATL and HAM/TSP are generally mutually
exclusive, and only a few cases with both disorders have been described.[21, 22]

o
o
o
o

o
o

o
o
o

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o
o

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o
o
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o

ATL develops in 2%-4% of individuals with HTLV-1 infection.[23] Four clinical subtypes of ATL have been
described.[24]
The acute form comprises 55%-75% of all ATL cases. It is characterized by a significantly increased
white blood cell count that is mostly made up of leukemic T cells. It also features generalized
lymphadenopathy.
The chronic form is characterized by absolute lymphocytosis (4 109/L or more), with T lymphocytosis
comprising more than 3.5 109/L. These laboratory findings persist for months to years in most
patients with chronic ATL. The lymphatic system may become involved.
Smoldering ATL is characterized by 5% or more abnormal T lymphocytes in peripheral blood, with a
normal total lymphocyte count.
The lymphoma type involves generalized lymphadenopathy and an absence of peripheral blood
involvement.
HAM/TSP develops in 1%-2% of individuals with HTLV-1 infection.[23]
The pathophysiology of HAM/TSP remains unclear, but, clinically, it can be defined as a slowly
progressive degenerative disease that primarily affects the corticospinal tracts of the thoracic cord.
Major pathologic findings of HAM/TSP may include inflammatory perivascular and parenchymal
infiltration by T-lymphocyte cells, leading to degeneration and fibrosis in the spinal cord. The degree of
infiltration is less than in other retroviral infections (eg, HIV infection), perhaps because of the slow
pathogenesis of the virus.[25]
Immunologic mechanisms may be involved in the development of HAM/TSP. This is likely mediated
through autoimmune processes or cytotoxic attack on the HTLV-1infected cells.
A higher provirus load increases not only the overall risk of HAM/TSP but also the likelihood that the
disease will progress more quickly.[26]
HTLV-1 is also associated with a broader spectrum of neurologic abnormalities that are not as severe
as HAM/TSP. It is not clearly established if individuals with the other neurologic abnormalities will
eventually develop HAM/TSP or will remain stable.[27]
HTLV-1associated uveitis/ocular manifestations[28, 29]
This is defined as the presence of HTLV viral sequences and HTLV-infected lymphocytes in the
vitreous fluid.
Additional ocular manifestations in individuals with HTLV-1 infection include retinal vasculitis,
choroidopathy, and keratopathy.
In 2013, a case report described unilateral intraocular invasion of ATL cells without systemic
symptoms following cataract surgery. Antibodies to HTLV-1 were positive, and the vitreous specimen
revealed flower cell infiltration with HTLV-1 DNA detected via polymerase chain reaction (PCR).[29]
HTLV-1associated infective dermatitis
HTLV-1associated infective dermatitis (IDH) is a chronic and severe dermatitis that mainly affects
children who have been infected with HTLV via vertical transmission.
There is an association between IDH and onset of HAM/TSP; 30% of Brazilian children with IDH
develop HAM/TSP in adolescence.[26]
Patients with IDH have a higher proviral load than asymptomatic carriers of HTLV-1. Primo et al
(2009) reported that the proviral load was not associated with age, duration of infection, duration of
breastfeeding, or severity of skin infection.[26]
Additional cutaneous diseases, which are found more frequently in HTLV-1 carriers than in
noncarriers, include aphthous stomatitis, eczema, and nongenital warts. [30]
Other diseases associated with HTLV-1 include Sjgren syndrome, polymyositis, and chronic
inflammatory arthropathy.[31, 23]
HTLV-1associated oral manifestations

In addition to Sjgren syndrome, other oral manifestations are becoming apparent. A study of
Brazilians with HTLV-1 infection showed the most common manifestations were xerostomia (26.8%),
candidiasis (20.8%), fissured tongue (17.9%), and loss of tongue papillae (17.9%). Patients with
HAM/TSP were 3 times more likely to have xerostomia than patients without HAM/TSP. [32] Similar
results were described by Lins et al.[20]
Garlet et al suggested an association between periodontitis and HTLV-1 in which HTLV plays a direct
role in deregulation of cytokines, resulting in an exaggerated immune response against the bacteria
causing periodontitis.[33]

HTLV-2
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
To date, no conclusive evidence has proven that HTLV-2 is an etiologic agent in any specific disease.
However, the following links have been suggested:

HTLV-2 infection may result in neurologic manifestations similar to the non-HAM complications of
HTLV-1 infection. Recent data suggest that HTLV-1 and HTLV-2 carry similar risks in terms of resulting
in non-HAM neurological illness.[34, 27]
Case reports have linked HTLV-2 infection with pneumonia, bronchitis, arthritis, asthma, and
dermatitis.[19]

HTLV-3 and HTLV-4

These HTLV subtypes were first isolated in 2005. HTLV-3 was initially isolated from a 62-year-old male
pygmy in southern Cameroon.[35] Now, with the aid of advancing laboratory technology, new strains are
quickly being identified. Individuals infected with HTLV-3 have all been asymptomatic, with a low proviral
load. HTLV-4 has been described in African bush meat hunters. In 2010, no evidence of HTLV-3 and
HTLV-4 infection was found in a sample of 1200 New York State subjects (human and simian subject
types) at risk for retroviral infection.[36]
Neither HTLV-3 nor HTLV-4 has been associated with specific diseases thus far, and further research is
ongoing. Given the ongoing discovery of subtypes and strains, it is not surprising that 28% of certain
populations in central Africa have been reported to have indeterminate HTLV serology results. [7]
The HTLV-3 label was initially applied to the virus that causes AIDS. However, further research found that
the pathogenesis and genetic makeup of the AIDS virus differed from HTLV-1 and HTLV-2.
Subsequently, the name was formally changed to HIV.

Epidemiology
Frequency
United States

HTLV-1
HTLV-1 infection is linked to immigrants, children of immigrants, sex workers, and injection drug users. [4]
Based on transfusion data from 2000-2009 among first-time donors, the prevalence of HTLV-1 was 5.1
cases per 100,000 population and was associated with female sex, older age, and black and Asian
race/ethnicity.[37]

HTLV-2
Based on transfusion data from 2000-2009 among first-time donors, the prevalence of HTLV-2 was 14.7
cases per 100,000 population and was associated with female sex, older age, nonwhite race/ethnicity,
lower educational level, and residence in the western and southwestern United States. [37]
In the United States, HTLV-2 infection affects Native American Indians. Some tribes have seroprevalence
rates as high as 13%.[19]
Intravenous drug users, in whom the seroprevalence is estimated to be about 20%, with a
disproportionate share occurring in African American injection drug users. [19]
International
Areas and small population clusters with high concentrations of HTLV-1 include the following:[4]

Southwest Japan: Japan has both low and high endemic microregions, with an estimated total 1.2
million HTLV-1 carriers.

Caribbean basin (Jamaica and Trinidad): This region has a prevalence of up to 6%.
Sub-Saharan African countries (Benin, Cameroon, Guinea-Bissau): These countries have a prevalence
of up to 5%.
South America
The Mashadi Jewish people of northern Iran and various immigrant populations from endemic areas
Areas and populations with high concentrations of HTLV-2 include the following:

Central and South America

North America and Europe, mainly among intravenous drug users

Mortality/Morbidity
Mortality and morbidity due to HTLV infections are primarily associated with diseases caused by HTLV-1,
namely ATL or HAM/TSP.
Infected individuals have a cumulative lifetime risk of 1%-4% of developing ATL or HAM/TSP.[4] The
latency period for ATL is typically 30-50 years. ATL is usually rapidly progressive and fatal, with a median
survival time of 2 years.[38]
HAM/TSP can occur as early as 3 months after blood transfusionrelated HTLV-1 infection. Three years
of latency is more typical, and 20-30 years is possible.
Biswas et al (2009) found that patients infected with HTLV - 2 missed more work days than patients with
HTLV-1, possibly because of isolated neurological manifestations and the increased rate of upper
respiratory infections and arthritis associated with HTLV-2.[27]

Sex
In endemic areas, HTLV-1 seropositivity is clustered in families, especially among women, suggesting
that transmission occurs more easily from men to women than from women to children. Determining the
sexual predominance of HTLV-2 infection is complicated by intravenous drug use in the study population.
Findings suggest that vertical transmission has a male predisposition, accounting for the predominance of
male HTLV-1 seropositivity in childhood. This, in turn, may explain the increased prevalence of ATL in
males because of a longer carrier state.[39]
HAM/TSP disproportionately affects females (with a female-to-male ratio as high as 2:1).[4]

Age
The prevalence of HTLV-1 and HTLV-2 infections increases with advancing age. The onset of ATL or
HAM/TSP is often delayed until later in life because of the prolonged latency state; vertical transmission is
associated with an elevated risk of ATL or HAM/TSP.

History
Acute human T-cell lymphotropic virus (HTLV) infection is rarely suspected or diagnosed.
Because of the low viral replication of HTLV, there are usually no clinical symptoms. Diagnosis may stem
from blood donation, testing performed because of a familial history of the infection, or a workup of adult
T-cell leukemia (ATL) or HTLV-1associated myelopathy/tropical spastic paraparesis (HAM/TSP) in
patients with consistent clinical manifestations. Suspected cases may prompt investigation for a history of
a recent blood-product transfusion or a nursing mother from an endemic area.
In considering HTLV infection, the most important historical information pertains to risk assessment.
Because detecting accurate seroprevalence in low-endemic populations is inherently problematic, it is
important to stratify a patient's risk. Screening enzyme immunoassays (EIAs) yield false-positive results in
more than 50% of cases in areas of low prevalence. Therefore, a high-risk individual is anyone who has
any of the following characteristics:

Has lived or lives in an endemic area (ie, Japan, the Caribbean, Central or West Africa, South America)
Is a Native American Indian
Has parents or sexual partners from an endemic area
Received blood-product transfusions in the United States before 1988
Has received blood transfusions anywhere that lacks active blood-bank screening
Has a history of injection drug use
Has sexual partners with a history of injection drug use
Has multiple sexual partners and does not use barrier protection
Has strongyloidiasis hyperinfection
The sequelae of latent HTLV infection generally occur decades after the initial infection, with the one
exception being the reports of HAM/TSP occurring within a few months of HTLV-1contaminated blood
transfusion.[40]

Patients with HAM/TSP may present with weakness and stiffness in the lower limbs (first presenting
symptom in 60% of cases[41] ), urinary incontinence, and/or severe lower back pain radiating to the legs. In
some cases, urinary frequency, urgency, incontinence, or retention precedes the paraparesis by many
years. Infected patients may also have symptoms of autonomic dysfunction leading to constipation, and,
in some cases, sexual dysfunction.
Symptoms of ATL are clinically broad and can manifest as fatigue, overt lymphadenopathy, thirst (due
to hypercalcemia), nausea, vomiting, fever, or abdominal pain.

Physical
There are no strict criteria established in terms of physical findings of HAM/TSP; however, the
following constellation of physical findings are typical and progressively worsen:[27]

Motor and sensory changes in the lower extremities

Clonus (may be evident); involuntary muscular contractions upon stretching of the muscles
Spastic gait in combination with weakness of the lower limbs
Detrusor insufficiency leading to bladder dysfunction
Preserved cognitive and upper-extremity neurological functions

The following isolated neurological symptoms have been also described in patients affected with
HTLV-1 or HTLV-2:[27]

Sensory neuropathies
Gait abnormalities
Bladder dysfunction
Erectile dysfunction
Mild cognitive defects
Motor abnormalities

ATL has the following 4 distinct types and clinical characteristics:

o
o
o
o

o
o
o
o
o
o

o
o
o
o
o
o

o
o
o

Acute ATL
Short and aggressive clinical course
Hypercalcemia, lytic bone lesions, pulmonary involvement, and lymphocytosis
Hepatosplenomegaly
Cutaneous lesions (indolent, nodular, indurated, exfoliative, or erythrodermal)
Smoldering ATL
Abnormal lymphocytes of 5% or less
Malignant cells with monoclonal proviral integration
Skin lesions
Pulmonary involvement (occasional)
No hypercalcemia, lymphadenopathy, or other visceral involvement
Possible elevation of the serum lactase dehydrogenase level
Chronic ATL
No hypercalcemia, ascites, or pleural effusion
No CNS, bone, or GI involvement
Possible lymphadenopathy, hepatomegaly, splenomegaly, skin or pulmonary involvement
A serum lactate dehydrogenase level that may be twice the reference range
Abnormal T-cell lymphocytes, greater than 3.5 X 109/L
Absolute lymphocytosis, greater than 4.0 X 109/L
Lymphomatous ATL
Lymphadenopathy in the absence of lymphocytosis
Histologic evidence of lymph node involvement required
Skin lesions clinically indistinguishable from cutaneous T-cell lymphomas

Causes
HTLV-1 and HTLV-2 are transmitted vertically from mother to child via breastfeeding or childbirth, from
person to person through sexual contact, and through blood contact, either by transfusion or by reuse of
injection equipment.

Blood transfusion is very effective at transmitting HTLV-1 and HTLV-2. Screening is standard policy in the
United States and in many other countries. The United States has been screening donated blood since
1988.

Retroviridae
Molecular biology
Lentivirus (HIV-1):

Enveloped, spherical to pleomorphic in shape, 80-100 nm in diameter.

GENOME

Monopartite, linear, dimeric, ssRNA(+) genome of 8,5 kb, with a 5-cap and
a 3poly-A tail. There are two long terminal repeats (LTRs) of about 600nt
long at the 5 and 3 ends. The LTRs contain the U3, R, and U5 regions.
There are also a primer binding site (PBS) at the 5end and a polypurine
tract (PPT) at the 3end.
GENE EXPRESSION

The integrated provirus utilizes the promoter elements in the 5LTR to drive
transcription. This gives rise to the unspliced full length mRNA that will serve
as genomic RNA to be packaged into virions or used as a template for
translation of gag, gag-pro (1 ribosomal frameshift), and gag-pro-pol (2
ribosomal frameshifts) polyproteins. The singly spliced mRNA encodes env
that is cleaved into SU and TM envelope proteins. Completely spliced mRNAs
encode Rex and Tax. Rex escorts unspliced and singly spliced RNAs out of
the nucleus of infected cells. Tax is a transcriptional activator that activates
viral and cellular genes. Four accessory proteins p27I, p12I, p13II and p30II
are also produced by alternative splicing of ORFs I and II.
REPLICATION

NUCLEAR

Lytic replication:
1. Virus attaches to host receptors through the SU glycoprotein. TM
glycoprotein mediates fusion with cell membrane.
2. Internalization and uncoating.
3. ssRNA(+) genome is copied into a linear dsDNA molecule by the reverse
transcriptase.
4. Nuclear entry of the viral dsDNA which is covalently and randomly integrated
into the cells genome by the integrase (=provirus).
5. Transcription of provirus by Pol II produces viral spliced and unspliced RNAs.
6. Translation of fully spliced viral RNAs produces tax and rex proteins.
7. Rex mediates nuclear export of the uncompletely spliced RNAs.
8. Translation of unspliced viral RNAs produces Env, Gag, Gag-Pro and Gag-ProPol polyproteins.
9. Assembly of the virion at the host cellular membrane and packaging of the
viral RNAgenome.
10.Budding through the plasma membrane and release of the virions.
11.Proteolytic processing of the precursors polyproteins by viral protease and
maturation of the virions.

Latent replication :
host chromosome

replication

as

provirus

integrated

in

the

TAXONOMYGroup VI: RNA reverse transcribing viruses

Family:

Retroviridae

Subfamily: Orthoretrovirinae
Genus:

Deltaretrovirus

SPECIESHuman T-lymphotropic virus 1 (HTLV-1)

HTLV-1 is divided in four subtypes:
A (Cosmopolitan)
B (Central African group)
C (Melanesian group)
D (New Central African group)
REFERENCE STRAINHuman T-lymphotropic virus 1
Sequence | Genome | ProteomeHOSTHuman.

CELL TROPISMCD4+ T-cells.

Epidemiology
GEOGRAPHYSouthwestern Japan, the Caribbean basin, Southeastern United States, Southern Italy, and
sub-Saharan Africa. Worldwide (intravenous drug users).

ASSOCIATED DISEASES
Asymptomatic
infection
(most
common).
Oncogenic retrovirus that can induce adult T-cell leukemia (ATL) which is a malignant
transformation of T-lymphocytes, and HTLV-1 associated myelopathy/tropical spastic
paraparesis (HAM/TSP) which is a chronic progressive neurological disease.
Its oncogenic potential may be mediated by tax, which trans-activates transcription of
proviralLTR, but also cellular oncogenes and the cellular gene encoding the growth factor
inerleukin-2 receptor.
TRANSMISSIONSexual contact, maternal-neonatal, blood
VACCINENone
Viral latency
Viral latency is the ability of a virus to remain dormant within the host cell,
sometimes establishing lifelong occult infection. Dependiong on the virus the
trigger of latency is highly variable, but the host cell context is always
determining. Latency can stop upon viral genome reactivation,often promoted
by stress cellular signals.
The viral genome can remain latent either as an episome or integrated in the
host chromosome. The latter allows replication of the viral genome during host
cell division. Virus latency is generally maintained by a few viral genes that
keep the viral genome silent and escape from host immune system.
Vertebrate viruses like some herpesviridae or retroviridae are able to infect
their host lifelong thanks to latency. This gives them an enormous advantage
for dissiminating in their host population: about 90% of human population
would be infected with varicella-zoster virus.
Virus

Family

Genus

Latent replication
form

Main site of latency

HHV-1,HHV-2

Herpesviridae

Simplexvirus

Circular episome

Sensory and cranial

nerve ganglia

HHV-3

Herpesviridae

Varicellovirus

Circular episome

Ganglia

HHV-4

Herpesviridae

Lymphocryptovirus Circular episome

Memory B-cells

HHV-5

Herpesviridae

Cytomegalovirus

Circular episome

Monocytes,lymphocytes

HHV-6

Herpesviridae

Roseolovirus

Circular episome

Monocytes

HHV-7

Herpesviridae

Roseolovirus

Circular episome

CD4+ T-cells

Ref.

HHV-8

Herpesviridae

Rhadinovirus

Circular episome

B-cells

HIV-1

Retroviridae

Lentivirus

Provirus

memory T-cells

HTLV-1

Retroviridae

Deltaretrovirus

Provirus

memory T-cells

Bacterial viruses which display a latent phase are called temperate, or

lysogenic. The term lysogenic refers to a host phenotype: the bacteria can be
spontaneously
lysed
by
the
latent
phage.
Bacteria such as E. coli and Salmonella contain multiple resident proviruses
whose variability in number and type constitutes a major source of diversity
between strains .Prokaryotic proviruses usually carry cargo genes encoding
traits adaptive to the host, among which arevirulence factors found in many
bacterial pathogens.
Viruses that have the ability to lie latent within a cell have two options when
infecting a cell: they can either enter the latency or the lytic pathway. The
decision between lytic and latent pathways is regulated by expression of
regulatory proteins part of a genetic switch system, usually repressor(s) as well
as proteins controlling the stability of the later. The outcome of the followed
pathways depends on the ratio of these key regulators. This ratio may be
determined by environmental factors such as the host cell type, its shape, or
the
nutriment
availability.
A well known genetic switch system is the one of bacteriophage lambda which
includes at least a repressor of the lytic promoter, a repressor of the latency
promotor and two key regulators
.
TAXONOMYGroup VI: RNA reverse transcribing viruses
Family:

Retroviridae

Subfamily: Orthoretrovirinae
Genus:

Deltaretrovirus

SPECIESHuman T-lymphotropic virus 2 (HTLV-2)

REFERENCE STRAINHuman T-lymphotropic virus 2
Sequence | Genome | Proteome
HOSTHuman
.CELL TROPISMCD8+ T-cells.
Epidemiology
GEOGRAPHYNative American populations. Intravenous drug users in Europe and United States.

ASSOCIATED DISEASESAsymptomatic infection (most common).

HTLV-2 can induce transformation of T-cells in culture, but does only very rarely induce adult T-cell
leukemia (ATL) which is a malignant transformation of T-lymphocytes. May induce atypical hair-cell
leukemia. HTLV-2 carries no viral oncogene. HTLV-2 carries no viral oncogene. Its oncogenic potential
may be mediated by tax, which transactivates transcription of proviral LTR, but also cellular genes.

TRANSMISSIONSexual contact, maternal-neonatal, blood

VACCINENoneTAXONOMYGroup VI: RNA reverse transcribing viruses
Family:

Retroviridae

Subfamily: Orthoretrovirinae
Genus:

Deltaretrovirus

SPECIESHuman T-lymphotropic virus 2 (HTLV-2)

REFERENCE STRAINHuman T-lymphotropic virus 2
Sequence | Genome | ProteomeHOSTHuman.CELL TROPISMCD8+ T-cells.
Epidemiology

GEOGRAPHYNative American populations. Intravenous drug users in Europe and United

States.
ASSOCIATED DISEASES
Asymptomatic
infection
(most
common).
HTLV-2 can induce transformation of T-cells in culture, but does only very rarely induce adult
T-cell leukemia (ATL) which is a malignant transformation of T-lymphocytes. May induce
atypical hair-cell leukemia. HTLV-2 carries no viral oncogene. HTLV-2 carries no viral
oncogene. Its oncogenic potential may be mediated by tax, which transactivates transcription of
proviral LTR, but also cellular genes.
TRANSMISSIONSexual contact, maternal-neonatal, blood

[Human retrovirus HTLV-1: descriptive and molecular

epidemiology, origin, evolution, diagnosis and associated
diseases].
[Article in French]

Gessain A.
Author information
Abstract
Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) was the first oncogenic human retrovirus
discovered in 1980. It is estimated that around 10-20 million people are infected with HTLV-1 worldwide.
However, HTLV-1 is not a ubiquitous virus. Indeed, HTLV-1 is present throughout the world with clusters
of high endemicity including mainly southern Japan, the Caribbean region, parts of South America and
intertropical Africa, with foci in the Middle East and Australia. The origin of this puzzling geographical
repartition is probably linked to a founder effect in certain human groups. In the high endemic areas, 0.5
to 50% of the people have antibodies against HTLV-1 antigens. HTLV-1 seroprevalence increases with
age, especially in women. HTLV-1 has 3 modes of transmission: mother to child, mainly through
prolonged breastfeeding (> 6 months); sexual, mainly but not exclusively occurring from male to female;
and by blood products contaminated by infected lymphocytes. HTLV-1 is mainly the etiological agent of
two very severe diseases: a malignant T CD4+ cell lymphoproliferation of very poor prognosis, named
adult T-cell leukemia/lymphoma (ATLL), and a chronic neuro-myelopathy named tropical spastic
paraparesis/HTLV-1-associated myelopathy (TSP/HAM). HTLV-1 is also associated with rare anterior
uveitis, infective dermatitis and myositis in some high HTLV-1 endemic areas. The repartition of the
different molecular subtypes or genotypes is mainly linked to the geographical origin of the infected
persons but not to the associated pathology. HTLV-1 possesses a remarkable genetic stability probably
linked to viral amplification via clonal expansion of infected cells rather than by reverse transcription. This
stability can be used as a molecular tool to gain better insights into the origin, evolution and modes of
dissemination of HTLV-1 and infected populations. HTLV-1 originated in humans through interspecies
transmission from STLV-1, a very closely related retrovirus, highly endemic in several populations of apes
and Old World monkeys.

[Human retrovirus HTLV-1: descriptive and molecular

epidemiology, origin, evolution, diagnosis and associated
diseases].
[Article in French]

Gessain A.
Author information
Abstract
Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) was the first oncogenic human retrovirus
discovered in 1980. It is estimated that around 10-20 million people are infected with HTLV-1 worldwide.
However, HTLV-1 is not a ubiquitous virus. Indeed, HTLV-1 is present throughout the world with clusters
of high endemicity including mainly southern Japan, the Caribbean region, parts of South America and
intertropical Africa, with foci in the Middle East and Australia. The origin of this puzzling geographical
repartition is probably linked to a founder effect in certain human groups. In the high endemic areas, 0.5
to 50% of the people have antibodies against HTLV-1 antigens. HTLV-1 seroprevalence increases with
age, especially in women. HTLV-1 has 3 modes of transmission: mother to child, mainly through
prolonged breastfeeding (> 6 months); sexual, mainly but not exclusively occurring from male to female;
and by blood products contaminated by infected lymphocytes. HTLV-1 is mainly the etiological agent of
two very severe diseases: a malignant T CD4+ cell lymphoproliferation of very poor prognosis, named
adult T-cell leukemia/lymphoma (ATLL), and a chronic neuro-myelopathy named tropical spastic
paraparesis/HTLV-1-associated myelopathy (TSP/HAM). HTLV-1 is also associated with rare anterior
uveitis, infective dermatitis and myositis in some high HTLV-1 endemic areas. The repartition of the
different molecular subtypes or genotypes is mainly linked to the geographical origin of the infected
persons but not to the associated pathology. HTLV-1 possesses a remarkable genetic stability probably
linked to viral amplification via clonal expansion of infected cells rather than by reverse transcription. This

stability can be used as a molecular tool to gain better insights into the origin, evolution and modes of
dissemination of HTLV-1 and infected populations. HTLV-1 originated in humans through interspecies
transmission from STLV-1, a very closely related retrovirus, highly endemic in several populations of apes
and Old World monkeys.

Figure 1
HTLV-1 virus structure and genome
(A) Schematic cross-section through a mature HTLV-1 particle depicting its structure and composition.
Reproduced with permission from reference 8 (Van Dooren, 2005). (B) Genomic organisation of HTLV-1.
(C) Viral messengers. The primary full-length messenger RNA encodes a large Gag-PR-Pol precursor
polyprotein, a singly spliced messenger encodes Env, and doubly spliced messengers encode the
regulatory proteins. Viral genes encoded by the plus and minus strand RNA are shown respectively
above and below the scale bar of the genomic length. HBZ=HTLV-1 bZIP-factor. LTR=long terminal
repeat.

Cellular Transformation by HTLV1

HTLV1 (Human T-Lymphotropic Virus-1) is the etiological agent for ATL (Adult T-Cell Leukemia) as well as for TSP
(Tropical Spastic Paraparesis) and HAM (HTLV1 Associate Myelopathy). Involvement of HTLV1 in ATL is dependent
on the virally-encoded transcriptional activator Tax (Transactivator X). Its ability to modulate the expression and
function of many cellular genes is reasoned to be a major contributory mechanism explaining HTLV1 mediated
transformation of cells. HTLV1 carries no viral oncogene. The oncogenic potential of the virus is linked to the
regulatory gene Tax. In activating cellular gene expression, Tax impinges upon several cellular signal-transduction
pathways, including those for CREB(cAMP Response Element-Binding Protein), NF-KappaB (Nuclear FactorKappaB), etc. Taxs transcriptional potential is linked to IKK (I-KappaB Kinase) Complex and MAP3Ks (MitogenActivated Protein Kinase Kinase Kinases) (Ref.1 & 2).Tax protein acts as a transcriptional transactivator which
functionally inactivates tumor suppressor proteins such as p53,CDKN2A (Cyclin Dependent Kinase Inhibitor-2A) and
inhibit cellular DNA repair. The HTLV1 Tax also interacts with a series of cellular proteins characterized by the

presence of a PDZ domain. One of them, Tax1BP3 (Tax1 (Human T-cell Leukemia Virus Type-1) Binding Protein-3),
binds to the C-terminal end of the HTLV1 Tax protein. HTLV1 Tax inhibitsp53-mediated Tax1BP2 (Tax1 (Human Tcell Leukemia Virus Type-1) Binding Protein-2) protein degradation. However, the effects of the Tax oncoprotein on
cell cycle progression remain unclear (Ref.3,4 & 5).
Tax influences the cellular capacity to correct damaged DNA. Tax through interactions with inhibitors
of CDKs (Cyclin-Dependent Kinases) and G1 Cyclins, deregulates the cell cycle control and removes the corrective
pauses. Indirectly, accelerating uncontrolled cell cycle progression. Tax is also considered to directly affect the
machinery for DNA repair. Thus it represses the expression of Pol-Beta (Polymerase DNA-Beta), an enzyme
important for base-excision repair and the MAD1L1 (Mitotic Arrest-Deficient-1 Yeast Homolog-Like-1) protein, a factor
likely critical for surveillance against aneuploidies (Ref.6 & 7). Attachment receptor for HTLV1 is the cellular glucose
transporter protein, GLUT1 (Glucose Transporter-1). The viral RT (Reverse Transcriptase) has strong affinity to
ssRNA. Upon removal of CA (Capsid) and Env (Envelope) glycoprotein, RT synthesizes the first strand of DNA that is
referred to as (-) DNA from viral ssRNA, plus-sense. The (-) strand is extended to the end of the viral RNA, which is
degraded by RNAaseH (Ribonuclease-H). The new (+) strand is then synthesized from the (-) strand. Reverse
transcription thus leads to the formation of dsDNA; RNAaseH destroys the remaining RNA. These viruses penetrate
via fusion, uncoat to core and then the Provirus is made through random integration. The Proviral ORFs (Open
Reading Frames), pX-III and pX-IV encode for regulatory proteins like Taxthrough alternative splicing of mRNAs
(Ref.8).
Tax initiates the immortalization and transformation of human thymocytes, cord blood lymphocytes and fibroblast
cells.Tax potently stimulates the expression of its cognate viral LTR (Long Terminal Repeat) that is U3-R-U5 (Unique
3-Repeat-Unique 5), as well as the promoters of several cellular genes. Tax has the ability to act through four
discrete cellular signaling pathways: CREB, NF-KappaB, AP-1 (Activator Protein-1) and SRF (Serum Response
Factor). The HTLV1 Taxprotein is predominantly a viral nuclear antigen with a well-defined NLS (Nuclear Localization
Signal) occurring in its N-terminal 48 residues. Tax protein co-localizes primarily in nuclear bodies with RNA
Polymerase-II , splicing complexes and specific transcription factors (Ref.5 & 9). A small amount of Tax protein
resides in the cytoplasm of mammalian cells. Thus, in modulating gene expression, Tax is envisioned to have
promoter-poximal (i.e. nuclear) as well as promoter-distal (i.e. cytoplasmic) effects. Tax by itself cannot associate
directly with DNA. However Tax dysregulates the expression of several cellular IE (Immediately Early) genes.
The Tax-mediated dysregulation of gene expression contributes importantly to its abrogation of normal cellular
metabolism. An early clue as to how HTLV1 affects cellular IE genes emerged from the finding that the DNAbinding SRF recruits the Tax protein to cellular promoters such as those for c-Fos (Cellular Oncogene Fos). The
CarG-box-tethered SRF binds Tax, thereby bringing the viral oncoprotein to the promoter. The C-terminal activation
domain of Tax then makes a contact directly with TATA-box bound TBP (TATA Box-Binding Protein)-protein resulting
in enhanced transcription. The HTLV1 LTR contains three imperfectly conserved 21 bp TxRE (Tax-Responsive)
sequences, each of which contains a core CREB binding sites flanked by 5G- and 3C-rich residues. Binding
of Tax to CREB enhances CREB-CREB homodimerization and heightens resulting association to DNA. Contact with
DNA results in proper folding of the Tax protein, which leads to a functional presentation of its C-terminal activation
domain. Correctly folded Tax protein is known to recruit through its amino acid residues 81-95 the transcriptional coactivators, CBP (CREB-Binding Protein) and p300. The p300-CBP associated factor, PCAF (p300/CBP-Associated
Factor) also binds to the C-terminal activation domain of Tax (Ref.1).
The biology of ATL cells is characterized by increased expression of genes coding for lymphokines and lymphokine
receptors. Expression of these genes is in part regulated by the NF-KappaB family of transcription
factors. Tax generally activates cellular transcription through a NF-KappaB-dependent pathway in a manner distinct
from its activation of CREB. The most frequently observed NF-KappaB form is that of a p65-p50 dimer, which is
ambiently retained in the cytoplasm byI-KappaB (Inhibitor of Kappa Light Chain Gene Enhancer in B-Cells) molecules
(Ref.9). In the commonly accepted paradigm, I-KappaB-Alpha and I-KappaB-Beta play major roles in
sequestering p65-p50 dimer in the cytoplasm. Phosphorylated I-KappaB-Alpha and I-KappaB-Beta subunits are then
targeted by Ubiquitin ligase component protein,Beta-TRCP (Beta-Transducin Repeat-Containing Protein); this
interaction leads to the Ubiquination and proteosomal degradation of the I-KappaBs. Upon removal of IKappaBs , NF-KappaB-molecules are freed to migrate from the cytoplasm into the nucleus. Within the nucleus, NFKappaBs bind promoter upstream DNA-motifs and activate the transcription of a diverse subset of target genes.
Because of Taxs predominant nuclear localization in cells, an initial mechanistic explanation for Tax-NFKappaB interplay invokes events within the nucleus (Ref.1).

Tax makes a contact with I-KappaB-molecules through similar ankyrin-motifs, thereby dissociating I-KappaBs from
cytoplasmically sequestered NF-KappaBs. This is the contact-dependent dissociation mechanism through
which Taxtargets I-KappaBs for proteosomal degradation. Besides the dissociation of I-KappaB from NF-KappaB,
another general mechanism of NF-KappaB activation describes site-specific phosphorylation of I-KappaB-Alpha,
followed by its ubiquitination and degradation (Ref.1). Biochemically, over-expressed Tax protein is present within the
large intracellularIKK-Alpha (Inhibitor of Kappa Light Polypeptide Gene Enhancer in B-Cells Kinase of Alpha), IKKBeta (Inhibitor of Kappa Light Chain Gene Enhancer in B-Cells Kinase of Beta) and IKK-Gamma (Inhibitor of Kappa
Light Chain Gene Enhancer in B-Cells Kinase of Gamma) complex. It is IKK-Gamma that binds Tax directly.
Thus, IKK-Gamma functionally adapts theTax oncoprotein into the large IKK-Alpha/IKK-Beta/IKKGamma complex. Tax activation of NF-KappaB occurs at a point down-stream of the small G-Proteins and
the TNFR (Tumor Necrosis Factor Receptor) interacting factors. At this juncture,Tax bridges the IKK-complex with
a MAP3K. MAP3K, as recruited by Tax, then phosphorylates IKK-Alpha/Beta leading to a cascade of events which
releases NF-KappaB for nuclear migration. Thus Tax activates the IKK and JNK (c-Jun Kinase) pathways in the
cytoplasm. The JNK pathway leads to the activation of c-Jun and c-Fos. Tax activation of NF-KappaB contributes to
cellular transformation (Ref.2).
Further signaling by Ifn-Gamma (Interferon-Gamma) stimulates anti-viral responses and tumor suppression through
the heterodimeric Ifn-GammaR (Ifn-Gamma Receptor). Signaling is initiated by binding of Ifn-Gamma to its receptor,
activating the receptor-associated JAK2 (Janus Kinase-2) tyrosine kinase to phosphorylate STAT (Signal Transducer
and Activator of Transcription) transcription factors that activate Ifn (Interferon) responsive genes. Molecular
chaperones that modulate or alter protein folding interact with different components of the Ifn Signaling Pathway. One
chaperone that modulates Ifnsignaling is DNAJA3 (DNAJ (HSP40) Homolog Subfamily-A Member-3) and a cochaperone for the HSPA8 (Heat Shock-70 KD Protein-8)/HSP70 (Heat-Shock Protein 70-KD), another molecular
chaperone. DNAJA3 binds to JAK2 and interacts with the Ifn-GammaR1 and Ifn-GammaR2. JAK2 and IfnGammaR2 associate with DNAJA3 andHSPA8/HSP70 to form a complex. DNAJA3 recruits HSPA8/HSP70 to the
receptor complex. DNAJA3 acts as a co-chaperone causing a conformational change in HSPA8/HSP70 that allows it
to interact with JAK2. The interaction ofHSPA8/HSP70 with JAK2 then inhibits the kinase activity
of JAK2 (Ref.10). DNAJA3 and HSPA8/HSP70 interact with other signaling proteins as well. One of this is Tax, a
protein encoded by the HTLV1 virus that binds to DNAJA3. DNAJA3represses NF-KappaB activation by blocking the
phosphorylation and inactivation of I-KappaBs by the IKKs. One of the actions of Ifn (Interferons) is to induce
apoptosis of infected target cells, in part through a mitochondrial dependent mechanism. An interaction
between Ifn signaling and HSPA8/HSP70 alter the Mitochondrial Apoptosis Pathway, playing a role in Ifn-mediated
apoptosis of infected or transformed cells. The HTLV1 Tax protein that interacts withHSPA8/HSP70 blocks
mitochondrial induced apoptosis, providing a protection against Ifn-mediated cellular defenses. The biological
activities of Ifn-Gamma mediated through the Ifn-GammaR are capable of activating the JAK/STAT
Pathway. DNAJA3 acts as a negative modulator of the JAK/STAT pathway (Ref.11).
HTLV1 induces a rather weak growth transformation of T-cells in the laboratory but, is probably never sufficiently
strong to induce T-cell leukaemia on its own. The virus naturally infects CD4+ T lymphocytes and can be transmitted
between close contacts through blood transfer or from mother to infant through cells in breast milk. In most cases the
infection is harmless. HTLV1 does not contain an oncogene and it is believed that the malignant change is the result
of interruption and deregulation of host DNA (Ref.1).

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