Human T-cell lymphotropic virus type 1 or human T-lymphotropic virus (HTLV-I), also called the adult T-cell lymphoma virus type 1, is a

retrovirus A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptas ...

of the

human T-lymphotropic virus The human T-lymphotropic virus, human T-cell lymphotropic virus, or human T-cell leukemia-lymphoma virus (HTLV) family of viruses are a group of human retroviruses that are known to cause a type of cancer called adult T-cell leukemia/lymphoma an ...

(HTLV) family that has been implicated in several kinds of diseases including very aggressive adult T-cell lymphoma (ATL),

HTLV-I-associated myelopathy Tropical spastic paraparesis (TSP), is a medical condition that causes weakness, muscle spasms, and sensory disturbance by human T-lymphotropic virus resulting in paraparesis, weakness of the legs. As the name suggests, it is most common in tropica ...

uveitis Uveitis () is inflammation of the uvea, the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and in ...

, ''

Strongyloides stercoralis ''Strongyloides stercoralis'' is a human pathogenic parasitic roundworm causing the disease strongyloidiasis. Its common name in the US is threadworm. In the UK and Australia, however, the term ''threadworm'' can also refer to nematodes of the ...

'' hyper-infection and some other diseases. It is thought that about 1–5% of infected persons develop cancer as a result of the infection with HTLV-I over their lifetimes. Adult T-cell lymphoma (ATL) was discovered in 1977 in Japan. The symptoms of ATL were different from other lymphomas known at the time. It was suggested that ATL is caused by the infection of a retrovirus called ATLV. Strikingly, ATLV had the transforming activity in vitro. These studies established that the retrovirus infection is the cause of ATL. The retrovirus is now generally called HTLV-I because later studies proved that ATLV is the same as the firstly identified human retrovirus called HTLV discovered by Bernard Poiesz and Francis Ruscetti and their co-workers in the laboratory of Robert C. Gallo at the

National Cancer Institute The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. T ...

. Infection with HTLV-I, like infection with other retroviruses, probably occurs for life. A patient infected with HTLV can be diagnosed when antibodies against HTLV-1 are detected in the serum.

Virology

HTLV-1 is a

belonging to the family

retroviridae A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...

and the genus

deltaretrovirus ''Deltaretrovirus'' is a genus of the ''Retroviridae'' family. It consists of exogenous horizontally transmitted viruses found in several groups of mammals. Examples are the ''Bovine leukemia virus'' and the human T-lymphotropic virus The hum ...

. It has a positive-sense RNA genome that is reverse transcribed into DNA and then integrated into the cellular DNA. Once integrated, HTLV-1 continues to exist only as a

provirus A provirus is a virus genome that is integrated into the DNA of a host cell. In the case of bacterial viruses (bacteriophages), proviruses are often referred to as prophages. However, proviruses are distinctly different from prophages and these te ...

which can spread from cell to cell through a viral synapse. Few, if any, free

virion A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's ...

s are produced and there is usually no detectable virus in the blood plasma though the virus is present in genital secretions. Like

HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

, HTLV-1 predominantly infects

CD4+ T cell The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...

s. The viral RNA is packed into the icosahedral capsid which is contained inside the protein inner envelope. The lipid outer envelope is of host cell origin but contains viral transmembrane and surface proteins. The virion is spherical in shape with a diameter of about 100 nm. Seven HTLV-1 genotypes are recognised—HTLV-1a through HTLV-1g. It is estimated that from 10 to 20 million people worldwide are infected; 3–8 million of them are in Africa. The most widespread genotype is type A. Types B, D, E, F and G have only been isolated from Central Africa. Type C is only present in Asia. Simian HTLV-1 genotypes are interspersed in between the human genotypes indicating frequent animal-human and human-animal transmission. The only human genotype that does not have a simian relative is A. It is thought that genotypes B, D, E, F and G originated in Africa from closely related STLV about 30,000 years ago, while the Asian genotype C is thought to have originated independently in Indonesia from the simians present there. Two subtypes are found in Japan: a transcontinental subgroup and a Japanese subgroup.

Epidemiology

The knowledge about HTLV-1 epidemiology is limited. The highest prevalence for any country has been detected in Japan (particularly in the southwest); in 2007 around 1% of Japan's population was infected. Two studies of blood samples from 1988 and 2006-07 showed the highest number of carriers was found in people born from 1927 to 1937 (people age 8 to 18 in 1945). The reasons for this extremely high prevalence are not known. In Taiwan, in Iran, and in

Fujian Fujian (; alternately romanized as Fukien or Hokkien) is a province on the southeastern coast of China. Fujian is bordered by Zhejiang to the north, Jiangxi to the west, Guangdong to the south, and the Taiwan Strait to the east. Its ca ...

(a Chinese province near Taiwan) the prevalence is 0.1–1%. The infection rate is about 1% in

Papua New Guinea Papua New Guinea (abbreviated PNG; , ; tpi, Papua Niugini; ho, Papua Niu Gini), officially the Independent State of Papua New Guinea ( tpi, Independen Stet bilong Papua Niugini; ho, Independen Stet bilong Papua Niu Gini), is a country i ...

, the

Solomon Islands Solomon Islands is an island country consisting of six major islands and over 900 smaller islands in Oceania, to the east of Papua New Guinea and north-west of Vanuatu. It has a land area of , and a population of approx. 700,000. Its capita ...

, and

Vanuatu Vanuatu ( or ; ), officially the Republic of Vanuatu (french: link=no, République de Vanuatu; bi, Ripablik blong Vanuatu), is an island country located in the South Pacific Ocean. The archipelago, which is of volcanic origin, is east of no ...

, where the genotype C predominates. In Europe HTLV-1 is still uncommon, although it is present in some high-risk populations, including immigrants and intravenous drug users. In Americas the virus is found in indigenous populations and descendants of African ancestry from where it is thought to have originated. The general prevalence is from 0.1 to 1%. In Africa the prevalence is not well known, but it is about 1% in some countries. HTLV-I infection in the United States appears to be about half as prevalent among

IV drug use Drug injection is a method of introducing a drug into the bloodstream via a hollow hypodermic needle, which is pierced through the skin into the body (usually intravenously, but also at an intramuscular or subcutaneous location). Intravenous ...

rs and about one-tenth as prevalent in the population at large as HIV infection. Although little serologic data exist, the prevalence of infection is thought to be highest among blacks living in the Southeast. A prevalence rate of 30% has been found among black intravenous drug users in

New Jersey New Jersey is a state in the Mid-Atlantic and Northeastern regions of the United States. It is bordered on the north and east by the state of New York; on the east, southeast, and south by the Atlantic Ocean; on the west by the Delaware ...

, and a rate of 49% has been found in a similar group in

New Orleans New Orleans ( , ,New Orleans

Alice Springs Alice Springs ( aer, Mparntwe) is the third-largest town in the Northern Territory of Australia. Known as Stuart until 31 August 1933, the name Alice Springs was given by surveyor William Whitfield Mills after Alice, Lady Todd (''née'' Al ...

, an estimated 5,000 people are infected. It is also high among the

Inuit Inuit (; iu, ᐃᓄᐃᑦ 'the people', singular: Inuk, , dual: Inuuk, ) are a group of culturally similar indigenous peoples inhabiting the Arctic and subarctic regions of Greenland, Labrador, Quebec, Nunavut, the Northwest Territories, and ...

of Northern Canada, in Japan, northeastern Iran. Peru, the Pacific coast of Colombia and Ecuador, and the Caribbean.

Transmission

HTLV-1 has three main routes of transmission. Vertical transmission is most common, through which an infected mother transmits the virus to her child. Interestingly, the risk to a fetus while inside the womb is minimal, given the virtual absence of viral particles in human plasma. Most vertical infection occurs through breastfeeding. About 25% of infants who are breastfed by infected mothers are infected, while less than 5% of children born to but not breastfed by infected mothers are infected. Sexual transmission is second-most common, whereby an individual infects another through exchange of bodily fluids. Some evidence has suggested that male-to-female transmission is more efficient than female-to-male transmission. For example, one study in Japan found a 61% transmission rate for males to females vs. a less than 1% rate for females to males. Least common is parenteral transmission through blood transfusion, with an infection rate of 44-63% estimated in one study, and needle sharing among intravenous drug users. With proper prophylaxis (e.g. breastfeeding counseling for mothers, condom use, and donor blood screening), rates of transmission can be effectively reduced. The importance of the various routes of transmission is believed to vary geographically. The research in discordant couples showed that probability of sexual transmission is about 0.9 per 100 person-years. * In Japan, the geographic clustering of infections suggest that the virus is more dependent on mother-to-child transmission. * In the Caribbean, the geographic distribution of the virus is more uniform, and it is more common among those with many sexual partners, indicating that sexual transmission is more common.

Tropism

The term viral tropism refers to which cell types HTLV-I infects. Although HTLV-1 is primarily found in CD4+ T cells, other cell types in the peripheral blood of infected individuals have been found to contain HTLV-1, including CD8+ T cells, dendritic cells and B cells. HTLV-I entry is mediated through interaction of the surface unit of the virion envelope glycoprotein (SU) with its cellular receptor

GLUT1 Glucose transporter 1 (or GLUT1), also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the ''SLC2A1'' gene. GLUT1 facilitates the transport of glucose acros ...

, a glucose transporter, on target cells.

Associated diseases

Malignancies

Adult T cell leukemia/lymphoma

HTLV-1 is also associated with

adult T-cell leukemia/lymphoma Adult T-cell leukemia/lymphoma (ATL or ATLL) is a rare cancer of the immune system's T-cells caused by human T cell leukemia/lymphotropic virus type 1 (HTLV-1). All ATL cells contain integrated HTLV-1 provirus further supporting that causal role o ...

and has been quite well studied in Japan. The time between infection and onset of cancer also varies geographically. It is believed to be about sixty years in Japan and less than forty years in the Caribbean. The cancer is thought to be due to the pro-oncogenic effect of viral RNA incorporated into host lymphocyte DNA. Chronic stimulation of the lymphocytes at the cytokine level may play a role in the development of the malignancy. The lymphoma ranges from a very indolent and slowly progressive type to a very aggressive and nearly uniformly lethal proliferative type.

Cutaneous T-cell lymphoma

There is some evidence that HTLV-1 is a causative agent of

cutaneous T-cell lymphoma Cutaneous T-cell lymphoma (CTCL) is a class of non-Hodgkin lymphoma, which is a type of cancer of the immune system. Unlike most non-Hodgkin lymphomas (which are generally B-cell-related), CTCL is caused by a mutation of T cells. The cancerous T ...

Inflammatory diseases

HTLV myelopathy/tropical spastic paraparesis

HTLV-1 is also associated with a progressive demyelinating upper motor neuron disease known as HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), characterized by sensory and motor deficits, particularly of the lower extremities, incontinence and impotence. Only 0.3 to 4% of infected individuals develop HAM/TSP, but this will vary from one geographic location to another. Signs and symptoms of HTLV myelopathy include: * Motor and sensory changes in the extremities * Spastic gait in combination with weakness of the lower limbs * Clonus * Bladder dysfunction(

neurogenic bladder Neurogenic bladder dysfunction, or neurogenic bladder, refers to urinary bladder problems due to disease or injury of the central nervous system or peripheral nerves involved in the control of urination. There are multiple types of neurogenic bladde ...

) and bladder cancer Other neurologic findings that may be found in

HTLV The human T-lymphotropic virus, human T-cell lymphotropic virus, or human T-cell leukemia-lymphoma virus (HTLV) family of viruses are a group of human retroviruses that are known to cause a type of cancer called adult T-cell leukemia/lymphoma and ...

include: *

Mild cognitive impairment Mild cognitive impairment (MCI) is a neurocognitive disorder which involves cognitive impairments beyond those expected based on an individual's age and education but which are not significant enough to interfere with instrumental activities of ...

Erectile dysfunction Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of mal ...

Arthropathy

HTLV-1 is associated with a rheumatoid-like

arthropathy An arthropathy is a disease of a joint. Types Arthritis is a form of arthropathy that involves inflammation of one or more joints, while the term arthropathy may be used regardless of whether there is inflammation or not. Joint diseases can be cla ...

, although the evidence is contradictory. In these cases patients have a negative

rheumatoid factor Rheumatoid factor (RF) is the autoantibody that was first found in rheumatoid arthritis. It is defined as an antibody against the Fc portion of IgG and different RFs can recognize different parts of the IgG-Fc. RF and IgG join to form immun ...

Uveitis

Studies from Japan demonstrated that HTLV-1 infection may be associated with an

intermediate uveitis Intermediate uveitis is a form of uveitis localized to the vitreous and peripheral retina. Primary sites of inflammation include the vitreous of which other such entities as pars planitis, posterior cyclitis, and hyalitis are encompassed. Intermed ...

. At onset the patients present with blurred vision and floaters. The prognosis is favorable—the condition usually resolves within weeks.

Opportunistic infections

Individuals infected with HTLV-1 are at risk for

opportunistic infection An opportunistic infection is an infection caused by pathogens ( bacteria, fungi, parasites or viruses) that take advantage of an opportunity not normally available. These opportunities can stem from a variety of sources, such as a weakened immu ...

s—diseases not caused by the virus itself, but by alterations in the host's immune functions. HTLV-1, unlike the distantly related retrovirus HIV, has an immunostimulating effect which actually becomes immunosuppressive. The virus activates a subset of T-helper cells called Th1 cells. The result is a proliferation of Th1 cells and overproduction of Th1 related cytokines (mainly

IFN-γ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...

and

TNF-α Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...

). Feedback mechanisms of these cytokines cause a suppression of the Th2 lymphocytes and a reduction of Th2 cytokine production (mainly IL-4, IL-5, IL-10 and IL-13). The result is a reduction in the ability of the infected host to mount an adequate immune response to invading organisms that require a predominantly Th2 dependent response (these include parasitic infections and production of mucosal and humoral antibodies). In the central Australian Aboriginal population, HTLV-1 is thought to be related to their extremely high rate of death from

sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...

. It is also particularly associated with bronchiectasis, a chronic lung condition predisposing to recurrent

pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...

. It is also associated with chronic infected

dermatitis Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved can ...

, often superinfected with ''

Staphylococcus aureus ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive ...

'' and a severe form of ''

'' infection called hyper-infestation which may lead to death from polymicrobial sepsis. HTLV-1 infection has also been associated with

Tuberculosis Tuberculosis (TB) is an infectious disease usually caused by ''Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in w ...

Treatment

Treatment of opportunistic infections varies depending on the type of disease and ranges from careful observation to aggressive chemotherapy and antiretroviral agents. Adult T cell lymphoma is a common complication of HTLV infection and requires aggressive chemotherapy, typically R-CHOP. Other treatments for ATL in HTLV infected patients include interferon alpha,

zidovudine Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child ...

with

interferon alpha The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...

and CHOP with

arsenic trioxide Arsenic trioxide, sold under the brand name Trisenox among others, is an inorganic compound and medication. As an industrial chemical, whose major uses include in the manufacture of wood preservatives, pesticides, and glass. As a medication, it ...

. Treatments for HTLV myelopathy are even more limited and focus mainly on symptomatic therapy. Therapies studied include

corticosteroids Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...

plasmapheresis Plasmapheresis (from the Greek πλάσμα, ''plasma'', something molded, and ἀφαίρεσις ''aphairesis'', taking away) is the removal, treatment, and return or exchange of blood plasma or components thereof from and to the blood circulati ...

, cyclophosphamide, and

interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten the ...

, which may produce a temporary symptomatic improvement in myelopathy symptoms.

Valproic acid Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those ...

has been studied to determine if it might slow the progression of HTLV disease by reducing viral load. Although in one human study it was effective in reducing viral load, there did not appear to be a clinical benefit. Recently however, a study of valproic acid combined with

showed a major decrease in the viral load of baboons infected with HTLV-1. It is important to monitor HTLV patients for opportunistic infections such as cytomegalovirus,

histoplasmosis Histoplasmosis is a fungal infection caused by '' Histoplasma capsulatum''. Symptoms of this infection vary greatly, but the disease affects primarily the lungs. Occasionally, other organs are affected; called disseminated histoplasmosis, it can ...

scabies Scabies (; also sometimes known as the seven-year itch) is a contagious skin infestation by the mite ''Sarcoptes scabiei''. The most common symptoms are severe itchiness and a pimple-like rash. Occasionally, tiny burrows may appear on the skin ...

pneumocystis pneumonia ''Pneumocystis'' pneumonia (PCP), also known as ''Pneumocystis jirovecii'' pneumonia (PJP), is a form of pneumonia that is caused by the yeast-like fungus '' Pneumocystis jirovecii''. ''Pneumocystis'' specimens are commonly found in the lungs of ...

, and

staphylococcal infection A staphylococcal infection or staph infection is an infection caused by members of the ''Staphylococcus'' genus of bacteria. These bacteria commonly inhabit the skin and nose where they are innocuous, but may enter the body through cuts or abrasio ...

HIV test HIV tests are used to detect the presence of the human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS), in serum, saliva, or urine. Such tests may detect antibodies, antigens, or RNA. AIDS diagno ...

ing should also be performed, as some patients may be co-infected with both viruses. Allogenic

bone marrow transplant Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produ ...

ation has been investigated in the treatment of HTLV-1 disease with varied results. One case report describes an HTLV-1 infected woman who developed chronic refractory eczema, corneal injury and adult T cell leukemia. She was subsequently treated with allogenic

stem cell transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to prod ...

and had complete resolution of symptoms. One year post-transplant, she has had no recurrence of any symptoms, and furthermore has had a decrease in her proviral load.

References

External links

International Retrovirology Association
* {{DEFAULTSORT:Human T-Lymphotropic Virus 1 Deltaretroviruses Infectious causes of cancer Sexually transmitted diseases and infections