Only a few retroviruses are linked to human tumors. The human T-lymphotropic virus (HTLV) group of retroviruses has probably existed in humans for thousands of years. HTLV-1 has been established as the causative agent of adult T-cell leukemia-lymphomas (ATL) as well as a nervous system degenerative disorder called tropical spastic paraparesis. It does not carry an oncogene. Three related human viruses, HTLV-2, HTLV-3, and HTLV-4, have been isolated but have not been conclusively associated with a specific disease. HTLV-1 and HTLV-2 share about 65% sequence homology and display significant serologic cross-reactivity.
The human lymphotropic viruses have a marked affinity for mature T cells. HTLV-1 is expressed at very low levels in infected individuals. It appears that the viral promoter enhancer sequences in the long terminal repeat may be responsive to signals associated with the activation and proliferation of T cells. If so, the replication of the viruses may be linked to the replication of the host cells—a strategy that would ensure efficient propagation of the virus.
The human retroviruses are transregulating (see Figure 1). They carry a gene, tax, whose product alters the expression of other viral genes. Transactivating regulatory genes are believed to be necessary for viral replication in vivo and may contribute to oncogenesis by also modulating cellular genes that regulate cell growth.
Fig1.Genetic organization of representative retroviruses. A: Nondefective, replication-competent viruses. Examples of retroviruses with simple and complex genomes are shown. An open rectangle shows the open reading frame for the indicated gene. If the rectangles are offset vertically, their reading frames are different. Horizontal lines connecting two rectangles indicate that this segment is spliced out. Simple genomes: ALV, avian leukosis virus (Alpharetrovirus); MLV, murine leukemia virus (Gammaretrovirus); MMTV, mouse mammary tumor virus (Betaretrovirus). Complex genomes: HIV, human immunodeficiency virus type 1 (Lentivirus); HTLV, human T-lymphotropic virus (Deltaretrovirus). B: Viruses carrying oncogenes. Several examples are shown, with the oncogene shaded; all are defective except RSV. Ab-MLV, Abelson murine leukemia virus (abl oncogene) (Gammaretrovirus); Ha-MSV, Harvey murine sarcoma virus (ras oncogene) (Gammaretrovirus); MC29, avian myelocytomatosis virus (myc oncogene) (Alpharetrovirus); Mo-MSV, Moloney murine sarcoma virus (mos oncogene) (Gammaretrovirus); RSV, Rous sarcoma virus (src oncogene) (Alpharetrovirus). The scale for genome sizes is shown at the bottom of each panel. (Modified with permission from Vogt VM: Retroviral virions and genomes. In Coffin JM, Hughes SH, Varmus HE [editors]. Retroviruses. Cold Spring Harbor Laboratory Press, 1997.)
There are several genetic subtypes of HTLV-1, with the major ones being subtypes A, B, and C (these do not represent distinct serotypes).
The virus is distributed worldwide, with an estimated 20 million infected individuals. Clusters of HTLV-associated disease are found in certain geographic areas (southern Japan, Melanesia, the Caribbean, Central and South America, and parts of Africa) (Figure 2). Although less than 1% of people worldwide have HTLV-1 antibody, up to 5% of the population in endemic areas may be seropositive.
Fig2. Subtypes of human T-lymphotropic virus type 1 are geographically distributed in endemic foci. A: Japan, India, the Caribbean, and the Andes; B: Japan and India; C: West Africa and the Caribbean; D: Central Africa; E: Papua New Guinea. (Courtesy of N Mueller.)
ATL is poorly responsive to therapy. The 5-year survival rate for patients with this cancer is less than 5%.
Transmission of HTLV-1 seems to involve cell-associated virus. Mother-to-child transmission via breastfeeding is an important mode. Efficiency of transmission from infected mother to child is estimated at 15–25%. Such early-life infections are associated with the greatest risk of ATL. Blood transfusion is an effective means of transmission, as are sharing blood-contaminated needles (drug abusers) and sexual intercourse.
Seroepidemiology has linked infection with HTLV-1 to a syndrome called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The primary clinical feature is development of progressive weakness of the legs and lower body. The patient’s mental faculties remain intact. HAM/TSP is described as being of the same magnitude and importance in the tropics as is multiple sclerosis in Western countries. Other HTLV-1-associated diseases include uveitis and infective dermatitis.
