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Retroviruses Other Than Human Immunodeficiency Virus
Definition
The human T-lymphotropic virus (HTLV) family has four members: HTLV-1, HTLV-2, HTLV-3, and HTLV-4. HTLV-1 causes two distinct types of disease: adult T-cell leukemia/lymphoma and several chronic inflammatory conditions, most notably HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 rarely causes neurologic symptoms and does not cause malignant disease. No disease associations have been established with HTLV-3 or HTLV-4.
The Pathogens
Within the taxa of RNA reverse-transcribing viruses, the HTLV viruses, along with bovine leukemia virus, are classified in the subfamily Retroviridae within the genus Deltaretrovirus (formerly termed Oncovirus ). The molecular structure of these viruses distinguishes them from the other group of complex human retroviruses, the human immunodeficiency retroviruses HIV-1 and HIV-2 ( Chapter 354 ), which are members of the genus Lentivirus . Both deltaretroviruses and lentiviruses are capable of prolonged asymptomatic infection. In vitro, however, HIV-1 and HIV-2 have cytopathic effects on human T cells, whereas HTLV-1 and HTLV-2 are noncytolytic and are capable of transforming T cells into immortalized cell lines. The HTLVs are diploid single-stranded RNA viruses that replicate through cDNA, which is a proviral intermediate, by reverse transcriptase, which is a viral polymerase.
Epidemiology
HTLV-1 is widely disseminated worldwide and is estimated to infect 5 to 10 million persons, with the aggressive T-cell malignant neoplasm adult T-cell leukemia/lymphoma developing in 2 to 6% and chronic inflammatory diseases, mainly HAM/TSP, developing in another 1 to 5% in their lifetime. Similar to HIV, molecular epidemiology suggests that the four major subtypes of HTLV identified in humans arose from separate interspecies transmission from simians to humans.
HTLV-1 has four major geographic subtypes: cosmopolitan subtype A; central African subtype B; Australo-Melanesian (Papua New Guinea, Melanesia, and Australian aborigines) subtype C; and central African/Pygmies subtype D. Central Africa also carries a few rare subtypes (E, F, G). Within the cosmopolitan group are four subgroups: transcontinental, Japanese, West African, and North African. The virus from Australo-Melanesia differs in its genome sequence from the Japanese and African strains by 5 to 10%, owing to independent evolution of the virus in these populations separated for tens of thousands of years. The genetic stability of HTLV-1 in comparison with HIV-1 reflects the observation that HTLV persists in the host mainly by proliferation of cells that contain the HTLV-1 provirus rather than infection of new cells. The HTLV subtypes differ phylogenetically by approximately 30 to 40% among each other.
HTLV-1 is not present in all human populations but rather clusters geographically: southern Japan; Melanesia; Australia (in aboriginal peoples); western, central, and southern Africa and, by the slave trade from Africa, the Caribbean and the United States in Black Americans; Central and South America; and the Mashhad region of Iran. HTLV-1 infection in Western Europe is predominantly linked to migration patterns, but the high prevalence of HTLV-1 infection in Romania remains unexplained. HTLV-1 is found in some indigenous populations of North America as well as in persons who migrated from the endemic regions. There is evidence of HTLV-1 infection in the Indian subcontinent and the southeastern seaboard of China, but the extent is uncertain. HTLV-2 is found in Native American people throughout North, Central, and South America, as well as in West Africa. HTLV-2 infections also occur in the United States and Europe in injection drug users, in whom the virus is spread by needle sharing and other injection practices as well as by sexual contact.
HTLV-3 and HTLV-4 are closely related viruses that were originally detected in Cameroon in humans who were bushmeat hunters. They have been detected in only a few persons, and their extent in West Africa is not yet known.
Routes of Transmission
HTLV-1 is transmitted zoonotically from bites of non-human primates, sexually, by breast-feeding, by transfusion, by injection drug use, and by solid organ transplantation ( Table 360-1 ).
TABLE 360-1
TRANSMISSION OF HTLV-1 AND HTLV-2
| MODE OF TRANSMISSION | HTLV-1 | HTLV-2 |
|---|---|---|
| MOTHER TO INFANT | ||
| Transplacental Breast milk |
Yes | Not known |
| Yes | Probable | |
| SEXUAL | ||
| Male to female Female to male Male to male |
Yes | Yes |
| Yes | Yes | |
| Yes | Not known | |
| PARENTERAL | ||
| Blood transfusion Injecting drug use |
Yes | Yes |
| Yes | Yes | |
| COFACTORS | ||
| Ulcerative genital lesions Cellular transfusion products Sharing of “works” ∗ |
Yes | Not known |
| Yes | Yes | |
| Yes | Yes | |
| ELEVATED VIRUS LOAD | ||
| Mother to infant Heterosexual |
Yes | Not known |
| Yes | Not known | |
HTLV = human T-lymphotropic virus.
Sexual Transmission
Sexual transmission of HTLV-1 from male to female, female to male, and male to male has been documented. HTLV-1 is almost exclusively cell associated: transmission between individuals requires transfer of infected lymphocytes, and cell-free blood products are not infectious. Coincidental infection with other sexually transmitted infections, particularly those associated with ulcerative and inflammatory genital lesions, amplifies the risk for transmission. In HTLV-1 infection, elevated viral load is linked to heightened transmission. In regions endemic for the virus, there is a characteristic age-dependent rise in HTLV-1 seroprevalence. This increase first becomes evident in the adolescent years; it is steeper in women than in men and continues in women after 40 years of age, whereas rates in men plateau around the age of 40 years. This pattern reflects more efficient male-to-female transmission. For HTLV-2, the rates for both genders are equal, suggesting that the kinetics of transmission differ between the two viruses.
Transmission by Breast-feeding
Transmission of HTLV-1 through breast-feeding is more efficient than in utero or perinatal transmission. Major risk factors that increase the efficiency of transmission include high proviral loads and increased duration of breast-feeding (>6 months). On average, 20% of infants breast-fed by HTLV-1-positive mothers seroconvert to HTLV-1, whereas only 1 to 2% of formula-fed infants become infected. By contrast, in utero and perinatal transmission accounts for virtually all mother-to-child HIV-1 transmission in the West, and breast-feeding accounts for an additional 15 to 20% of infant HIV infection in Africa. HTLV-2 is detectable in breast milk, and, as with HTLV-1, breast-feeding accounts for many childhood infections.
Transfusion, Solid Organ Transplantation, and Injection Drug Use
Parenteral transmission, through unscreened transfusion, solid organ transplantation, or injection drug use, is a significant source of HTLV infection. Among U.S. blood donors who are confirmed to be HTLV positive, the major risk factors are intravenous drug use, birthplace in parts of the Caribbean or Japan where the virus is endemic, and sexual contact with a person with this profile.
In the United States, more than 50% of HTLV infections among screened potential blood donors are due to HTLV-2, and effective screening can eliminate transfusion-related infection. By comparison, HTLV-1 predominates in other countries where HTLV infections are present. Among injection drug users, most HTLV infections also are due to HTLV-2.
Both HTLV-1 and HTLV-2 are transmitted only by direct cell-to-cell contact, through a specialized structure called a virologic synapse, whereas HIV-1 is transmitted either through a virologic synapse or by cell-free virus in plasma or plasma products. Approximately 50% of the recipients of cellular products of HTLV-1– or HTLV-2–positive blood seroconvert, compared with more than 95% for HIV-1.
The only documented illness linked to HTLV-1 or HTLV-2 transfusion-associated transmission is the HTLV-associated demyelinating neurologic syndrome HAM/TSP. Leukemia has not been associated with transfusion of HTLV-positive blood. Solid organ transplantation from HTLV-1–infected donors is associated with a high rate of transmission and rapid onset and progression of HAM/TSP.
Other Means of Infection
Casual contact, without sexual contact or exposure to cellular blood contents, is not a source of infection. There are limited data on health care and laboratory workers who experience a needlestick or skin or mucous membrane exposure. However, the risk of infection should be assessed from the clinical history, in particular of sexual contacts and blood transfusions, and potential seroconversion should be monitored.
Coinfection with HIV
Coinfection with HTLV-1 and HIV-1 appears to increase the progression to acquired immunodeficiency syndrome (AIDS) through unexplained mechanisms, possibly related to the cell-proliferative effects of HTLV-1 on HIV-1–infected T cells and/or coreceptor expression modulating CD4 cell permissiveness. Elevated CD4 counts due to HTLV-1 in patients with HIV/HTLV-1 coinfection can underestimate the degree of immune suppression. HAM/TSP and adult T-cell leukemia/lymphoma can occur in coinfected patients, but the clinical manifestations of HIV/HTLV coinfection in the era of early and fully suppressive antiretroviral therapy are poorly understood.
Pathobiology
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