The human T lymphotropic viruses, type I (HTLV-I) and type II (HTLV-II) are members of a family of mammalian retroviruses that have similar biological properties and a tropism for T lymphocytes (1-3). HTLV-I is endemic in a number of well-defined geographic areas, where infection is associated with adult T cell leukemia (ATL), a malignancy of mature T lymphocytes, a chronic encephalomyelopathy known both as HTLV-I-associated myelopathy and tropical spastic paraparesis (HAM/TSP), and a characteristic uveitis, HTLV-I-associated uveitis (HUV). HTLV-II infection has been shown to be endemic in a number of American Indian populations, and high rates of infection have also been documented in intravenous drug abusers (IVDAs) in North America, certain European nations, and Southeast Asia. Although the role of HTLV-II in human disease has yet to be clearly defined, there is accumulating evidence that like HTLV-I, infection may also be associated with rare lymphoproliferative and neurological disorders. In this article, the molecular epidemiology of HTLV-II infection is reviewed, and the pathogenic properties and clinical features that have been tentatively associated with infection are summarized.
HTLV-II infection has been shown to be endemic in a large number of native American Indian populations (Fig. 1). In North America these include the Navajo and Pueblo Indians of New Mexico (4-6) and the Seminole Indians in Florida (7). Infection is also endemic in the Guaymi Indians of Panama (8) and in a number of geographically and culturally distinct populations in South America. These include the Wayu, Guahibo, and Tunebo groups in Columbia (9-11), the Toba and Mataco Indians of Argentina (12,13), and at least five Brazilian populations, the Kayapo (14-16), Munduruku (16), Tyrio (16), Arara do Laranjal (16), and Kraho (14). In addition, preliminary studies on small groups of individuals from Chile have indicated there may also be endemic infection in that country (17). Importantly, several of the Southern American Indian populations have until recently remained relatively isolated and have had little interaction with individuals either from other indigenous groups or from urban areas of the countries involved. This suggests that HTLV-II is almost certainly an ancient infection of American Indian groups, and it seems possible that the virus may have either existed in its present form(s) or, possibly, evolved from a proto-HTLV during the migrations of the ancestors of these populations from the Old World many thousands of years ago.
At present, the viruses present in these endemic regions have not been completely characterized, and it is unclear if they are genetically heterogeneous. However, studies on both IVDAs and certain American Indian groups have shown that there are at least two major molecular subtypes of the virus, which have been designated HTLV-IIa and HTLV-IIb (3,18-21). The two subtypes can be readily differentiated by restriction endonuclease mapping and by nucleotide sequencing with phylogenetic analysis of the proviruses. The divergence of nucleotide sequence ranges from 4 and 7%, depending on the region of the provirus examined (3,19,21). The greatest inter- and intrasubtype divergence occurs in the long terminal repeat (LTR), and as such, analysis of this region has been the most rewarding in phylogenetic studies. A typical phylogenetic analysis involving a 449-nucleotide region of the LTR of a total of 30 virus isolates is shown in Fig. 2(22). In this study we analyzed 10 HTLV-IIa isolates. With the exception of KT, which was from a prostitute from Ghana (23), all were from North America. Twelve HTLV-IIb isolates were included. These included isolates from three American Indian groups (G12, Guaymi; FH, SC, and AG, Pueblo; WY, Wayu) and from individuals residing in urban areas of North America, the majority of whom were IVDAs. The analysis shows the distinct phylogenetic clustering of the two molecular subtypes of the virus. It can also be seen that within the HTLV-IIb subtype, the three Indian groups clustered into three distinct groups. As it is likely that these Indian groups originated from a common Paleo-Indian ancestor(s), this observation may reflect the molecular changes that may have occurred over the thousands of years during their separation. The phylogenetic analysis also included samples from the Kayapo Indian group, which resides in the Amazon region of Brazil, and samples from infected IVDAs living in urban areas of that country (Fig. 2). It can be seen that these samples, while being much more related to HTLV-IIa than HTLV-IIb, formed a distinct phylogenetic group, suggesting that they might represent a distinct HTLV-IIa molecular variant (22).
The studies of the virus subtypes in urban areas and Indian groups are still incomplete but can be summarized as follows. Whereas HTLV-IIa has been clearly shown to be the predominant infection in IVDAs in urban areas of North America (8,21,24), HTLV-IIb predominates in the Paleo-Indian groups (3,20,21). To date, HTLV-IIb has been shown to be the exclusive infection in the Guaymi of Panama (25), the Wayu of Columbia (26,27), and the Toba and Mataco groups of Argentina (13). In contrast, studies of Indian populations in North America have shown that whereas HTLV-IIb infection appears to predominate, a number have infection with both subtypes (20). It seems possible that these populations may have endemic infection with one subtype, which would also appear to be HTLV-IIb in the Pueblo and Seminole groups, and that the second has been introduced only recently by interactions with individuals who had other risk factors for infection. In this respect it has also recently been reported that the Wayu of Columbia may be infected with two IIb types (27). However, it is also unclear if both of these might represent endemic infection or whether one or even both may have recently been introduced into that population.
As noted above, in contrast to the studies on the aforementioned Indian groups, we have recently demonstrated that the Kayapo Indians, an indigenous population of the Amazon region of Brazil, are infected with a distinct variant of the HTLV-IIa subtype (16). Preliminary studies from our laboratory have also shown the Munduruku, which are a culturally and linguistically distinct population also residing in the Amazon region, are also infected with a HTLV-IIa variant that is phylogenetically very closely related to the virus infecting the Kayapo (R. Ishak and W. W. Hall, unpublished). This observation together with the identification of a closely related virus in the Brazilian IVDAs (Fig. 2) suggests that this variant is indigenous to this geographical region. Surprisingly there has been no identification of the prototype HTLV-IIa viruses present in urban areas of North America in a North American Indian group. However, it might be expected that such a focus may exist, or has at some time in the past, as this is most probably the origin of infection by this subtype in IVDAs in urban areas of the country.
The finding of greater nucleotide divergence in the LTR compared to other regions of the provirus is similar to what has been reported for HTLV-I (28,29). In HTLV-I, this has been exploited to allow the development of restriction fragment length polymorphism (RFLP) methods to permit a more detailed classification of the virus (30). These studies have demonstrated that while there appears to be no correlation of virus sequence or RFLP group with a particular clinical outcome, this does reflect the geographical origin of the virus. We and others have recently carried out similar RFLP analysis of the LTR region of HTLV-II isolates (24,31), and preliminary studies have indicated that such methods do allow a further classification of the subtypes into a number of distinct RFLP groups. However, initial studies suggest that RFLP analysis of the HTLV-II LTR may be much more complex than that of HTLV-I. Future studies should determine how well the methods may correlate with the origin of the virus isolates, their importance in the analysis of the viruses in endemic areas, and if such a system will prove to be a valuable tool in the classification of HTLV-II.
Until recently, endemic HTLV-II infection has been considered to be essentially restricted to the Americas, and this has led to the suggestion that it should be considered a virus of the New World (14). However, several studies have demonstrated that infection also exists in Africa (23,32-42). While this in some instances is almost certainly sporadic, having probably been recently introduced, there is also evidence that there are populations who may have endemic and possibly ancient infection. HTLV-II infection has been documented in at least two geographically distinct Pygmy populations in Cameroon and Zaire (34-37,41). Preliminary molecular characterization of the viruses has shown that in each case this involved subtype HTLV-IIb, with a remarkable conservation of nucleotide sequence between the viruses and HTLV-IIb isolates in American Indian groups and urban IVDAs. The Pygmies are considered to be one of the oldest inhabitants of Africa, suggesting that infection may have been present in this region for many thousands of years. Similarly the identification of infection in three family members over two generations living in a remote area of Gabon who were apparently without identifiable risk factors for infection supports the possible existence of other endemic foci (40).
Recently we have also documented HTLV-IIa infection in three elderly females living in Mongolia (43), and these exhibited marked conservation of nucleotide sequence with the HTLV-IIa present in urban areas of North America. Further studies are required to define better HTLV-II infection in this geographical region and, in particular, to determine if this might represent endemic infection or whether it might have been recently introduced. These investigations may provide important insights not only on the origin of the virus in native American Indian populations, but also on the origin of these populations themselves. Indeed there is strong evidence based on analysis of mitochondrial DNA that present-day Indian groups and certain Mongolian populations may have had common ancestors (44).
In addition to endemic foci, high rates of HTLV-II infection have also been documented in certain IVDAs in urban areas of North America (45,46), and in several European countries (47-49), and in Southeast Asia (50). In general, as has been noted in endemic areas, rates of infection usually increase with age. The reasons for this are unclear, but in all probability this most likely reflects an increased risk of infection, which might be expected as a result of an increase in the total number of years of drug abuse. Characterization of the viruses in IVDAs in the United States has shown that HTLV-IIa infection is much more prevalent than HTLV-IIb (18,21). Subtype analysis of the European samples has given variable results. Whereas HTLV-IIb is clearly more prevalent in Spain and Italy (51,52), HTLV-IIa is found almost exclusively in Sweden (53). Recently we have also documented very high rates of infection, ≈60%, in IVDAs in Ho Chi Minh City in former South Vietnam (50). Since it is now clear that infection was already present in IVDAs in North America in the early 1970s (54,55), this suggests that HTLV-II may well have been introduced to Vietnam by American servicemen during the Vietnam War in the 1960s and early 1970s. This view is indirectly supported by the finding that as in the United States, HTLV-IIa infection is also much more common than HTLV-IIb in IVDAs in Vietnam. While the origin of HTLV-II in IVDAs in North America remains unclear, it seems possible that this originated from interactions with individuals from one or more of the aforementioned Indian groups, most probably those in North America. It also seems highly likely that infection in European IVDAs may be related to interactions with their North American counterparts.
Although the modes of transmission of HTLV-II are less well established than those of HTLV-I, the evidence to date suggests that while they are probably identical, there may be differences in the relative efficiencies of transmission. HTLV-I is transmitted by transfusion of contaminated cellular blood products, by injection using syringes or needles that contain contaminated blood, sexually, and vertically from mother to child (56-59). HTLV-II infection has been clearly documented following transfusion of contaminated cellular blood products (60-62). However, the relative efficiency of transmission following transfusion compared to HTLV-I remains unclear. Transmission of HTLV-I by contaminated cellular blood products is extremely efficient, and it has been shown in endemic regions of Japan that >60% of recipients of such products become infected (56). Studies from the United States on infection rates following transfusion of HTLV-seropositive blood products have yielded contrasting results. One study suggested that transmission rates may be lower than that observed in Japan, with some 20% or recipients becoming infected (61). In contrast, a second study from New York suggests that the infection rates following transfusion of HTLV-II-contaminated products are similar to that of HTLV-I in Japan (62). It is almost certain that the high rates of infection of HTLV-II in IVDAs are due to contaminated blood in syringes and other related drug-related paraphernalia. It remains unclear why HTLV-II infection in IVDAs is so much more prevalent than HTLV-I. However, it is possible that this may reflect the different cellular tropisms of the two viruses, possibly higher viral loads in individuals with HTLV-II infection, or perhaps a greater stability of HTLV-I- or HTLV-II-infected cells.
Sexual transmission also appears to be clearly an important route of HTLV-II infection (63). Studies in HTLV-I endemic areas have shown that heterosexual transmission appears to be more efficient from male to female, and it has been estimated that the chance of transmission of HTLV-I to wives of infected men is ≈60%. In contrast, transmission from seropositive women to their uninfected husbands has been reported to be 0.4% (57), and this adequately accounts for the much higher seropositivity rates in elderly women in HTLV-I endemic areas. In studies of the Kayapo of Brazil (16) and the Guaymi of Panama (64), high but equivalent rates of infections were found in both males and females, and infection rates were found to increase with age. This not only supports the view that sexual transmission of HTLV-II is an important route, but also may suggest that there may be equivalent efficiencies of transmission between the sexes.
Recent studies have also shown that vertical transmission of HTLV-II is an important route of infection. In HTLV-I endemic areas, mother-to-child transmission occurs predominantly through breast-feeding (65,66), and as many as 25% of breast-fed infants become infected. Perinatal infection occurs much less frequently, with ≈5% of those children born to infected mothers who did not breast-feed becoming infected (66). HTLV-II has been detected in breast milk of infected mothers (67), and there has been one reported case where transmission of HTLV-II appears to have resulted directly from breast-feeding (68). Studies in HTLV-II endemic areas certainly support the importance of this route of transmission. In the Guaymi there is a much higher rate of HTLV-II infection in children born to infected mothers compared to uninfected mothers (64). In our own studies we found that >20% of Kayapo children under the age of 9 were seropositive, and direct studies of family members suggested that the risk of transmission of the virus from an infected mother to her child was between 30 and 50% (16). It should be cautioned that the true rates of transmission by breast-feeding can be difficult to assess, as children of the Kayapo are often breast-fed by other lactating women in the community. The relative importance of infection via breast-feeding compared to that occurring in utero and/or in the perinatal period remains unknown. However, the latter would seem to be less important, as a study has shown that of 20 children born to 19 HTLV-II-infected mothers who did not breast-feed, none became infected (69).
At present it is unclear if there are differences in the phenotypes of the two known subtypes of HTLV-II. As noted above, several studies have shown that there is some 4-7% divergence in nucleotide sequence between the subtypes, depending on the regions of the provirus analyzed. To determine if this may result in differences in the biological properties or phenotype of the two subtypes, we have focused our studies on the LTR and pX regions. Analysis of the LTR demonstrated that, in addition to a large number of nucleotide substitutions, this region also had several deletions and insertions. However, none of these changes involved the biologically important regions such as the TATA box, poly(A) site, 21-bp repeat sequences, and primer binding site (PBS) located downstream from the LTR (19), and as such, the differences would not be expected to result in major functional differences.
In contrast to the LTR, several studies have suggested that there may be important differences between the subtypes in the pX region. The pX region encodes the important regulatory proteins, tax and rex. Tax is a potent transcriptional activator of the provirus LTR and, in addition, can transactivate and induce the expression of a number of heterologous cellular genes, some of which are known to be involved in T cell growth, proliferation, and possibly transformation (2). Nucleotide sequence analysis of all IIb isolates examined so far has shown there are nucleotide substitutions in the 3' end of the tax sequence which would abrogate the expected stop codon present in the IIa subtypes (3,25,70). This change would be expected to result in the synthesis of an extended tax protein that would have an additional 25 amino acids at the carboxy terminus of the molecule (Fig. 3). Recently we have also found that the variants seen in the Brazilian populations also have an extended tax protein, suggesting that while these viruses, while being phylogenetically closely related to HTLV-IIa, may be phenotypically more similar to HTLV-IIb (22). Of note, while the additional 25 amino acids would make the tax-b protein the same size as the HTLV-I tax, there is relatively little homology in the carboxy terminus of the two viruses. Studies currently under way should determine if there are differences in the transactivation properties of the HTLV-IIa and extended tax proteins, as this may have important implications for our understanding of the relative pathogenic properties of the virus subtypes. In preliminary studies from our laboratory we have obtained evidence that the extended tax protein is indeed a much more potent transactivator of the virus LTR (22). Further studies are in progress to determine the significance of this in vivo by establishing transgenic animals expressing the different tax proteins and mutants thereof.
PATHOGENIC PROPERTIES AND CLINICAL FEATURES OF INFECTION
On the basis of the known disease associations of HTLV-I, it might be anticipated that HTLV-II infection would also be associated with both lymphoproliferative and neurological disorders. While this may be correct, no disorders have as yet been consistently associated with infection. With respect to lymphoproliferative disorders, the first two isolations of the virus (HTLV-II-Mo and HTLV-II-NRA) were from patients with hairy cell leukemia (HCL) (71,72). Although subsequent studies employing both serological and molecular methods have failed to demonstrate the involvement of HTLV-II in HCL, reevaluation of one of the patients (NRA) showed that this patient also had a coexisting asymptomatic CD8+ lymphoproliferative process. Southern hybridization methods showed that there was oligoclonal integration of the provirus in CD8+ T lymphocytes but not in the malignant “hairy” cells (73). This was the first clear demonstration of an association of HTLV-II infection with a lymphoproliferative disorder and, also, suggested the possible association of the virus with disorders involving CD8+ T lymphocytes. Subsequently, we reported the development of unusual skin disorders in two IVDAs who were concomitantly infected with HIV and HTLV-II (74). Both patients presented with a severe erythroderma with subsequent exfoliation of the skin. While examination of peripheral blood did not reveal abnormal cells or evidence of a lymphoproliferative process, histopathological examination of the skin lesions revealed similarities to certain cutaneous T cell leukemia/lymphomas (CTCLs) and, in particular, smoldering ATL. Specifically there was diffuse infiltration of the dermis with mature T lymphocytes, with sparing of the epidermis. However, the infiltrating cells were found to be mature CD8+ T lymphocytes and not CD4+, which is usually observed in ATL and the CTCLs. Recently a second report also described two IVDAs infected with both HIV-I and HTLV-II presenting with a strikingly similar disorder (75). The two independent descriptions of similar disorders are unlikely to be coincidental, and while one cannot directly attribute these disorders solely to HTLV-II infection, we are unaware of reports of similar disorders occurring in individuals infected only with HIV. Moreover, the previously described association of infection with CD8+ lymphoproliferation supports the view that the virus may have had at least some role in their pathogenesis.
The clinical observations of a possible involvement of HTLV-II with disorders of CD8+ T lymphocytes suggested that the virus may have a preferential tropism for this cell type in vivo. This was confirmed in a study employing the PCR to detect provirus in highly purified populations of mononuclear cells from infected individuals (76). Of the nine individuals initially evaluated, HTLV-II was detected exclusively in the CD8+ T lymphocytes in eight. In the remaining individual, virus was also detected in CD4+ T lymphocytes. Infection of B cells or monocytes was not demonstrated. These findings contrast sharply with studies on HTLV-I where the virus was shown to have a preferential tropism for CD4+ T lymphocytes but, on occasion, could also infect CD8+ cells (77). Importantly, the preferential tropism of HTLV-II for CD8+ lymphocytes is shared by both subtypes of the virus. While a subsequent study has also confirmed the preferential tropism of HTLV-II for CD8+ T lymphocytes (78), this also suggested that CD4+ cells are very frequently infected. Moreover, it was also suggested that in certain circumstances the virus also infects B cells, natural killer cells, and monocytes in vivo. The reasons for the differences in the two studies are unclear but may well reflect the homogeneity of the cell populations employed and perhaps the sensitivity of the polymerase chain reaction used for provirus detection.
Recently, there have been reports describing an association of HTLV-II infection with disorders of large granular lymphocytes. These included one patient with large granular lymphocytosis (79) and one with large granular lymphocytic leukemia (LGL) (80). In the former study it was shown that the provirus was not present in the large granular lymphocyte population but, instead, was found primarily in the CD8+ T lymphocyte population. This is similar to the situation described above in the case of HCL and is consistent with the view that in vivo the virus preferentially infects the CD8+ T cell population. At present it is unclear if infection in both of these patients may have been coincidental, or whether this may have contributed, to the development of their lymphoproliferative disorders. However, a subsequent study of 51 patients with LGL demonstrated HTLV-II infection in only 1, suggesting that infection in this condition is quite rare (81).
The literature also contains one report of a case of mycosis fungoides with associated HTLV-II infection (82). While this patient apparently had biopsy-proven disease, no analysis was carried out to determine the phenotype of the infiltrating lymphocytes. Similarly no attempts were made to determine the tropism of the virus either in the infiltrating cells or in the peripheral blood. As such, it is also unclear if the HTLV-II played any role, direct or indirect, in this particular case.
The finding that HTLV-II preferentially infects CD8+ T lymphocytes in vivo would appear to have important implications for understanding the role of the virus in lymphoproliferative disease and would suggest that, if HTLV-II plays a role in such disorders, they might be expected to be quite different from those known to be associated with HTLV-I. It can be speculated that infection of CD8+ lymphocytes could produce lymphoproliferative disorders by at least two mechanisms. Infection of population of CD8+ T lymphocytes could directly result in expansion of the infected cell population. It could be anticipated that this might result not only in a clinically benign, but perhaps eventually in a neoplastic disorder. Alternatively, infection might lead indirectly to the proliferation of cell populations that are not infected. This might be mediated by lymphokines or growth factors, which are known to be produced by HTLV-II-infected T lymphocytes in vitro (83,84). This could well explain the development of the described LGL disorders and, perhaps, the case of HCL from which HTLV-II was originally isolated.
The preferential tropism of HTLV-II for CD8+ T lymphocytes may also have implications for disease outcome in individuals who have concomitant HIV infection. It has been shown that as many as 12.5% of HIV-infected IVDAs in the New York City area are infected with HTLV-II (3). Studies have suggested that individuals concomitantly infected with HTLV-I and HIV are at significantly increased risk for development of acquired immunodeficiency syndrome (AIDS) compared to individuals infected with HIV alone (85). This apparent increase in HIV pathogenicity may be expected because of the common tropism of the viruses for CD4+ T lymphocytes. In view of the different tropism of HTLV-II, it might be expected that this infection does not influence the natural history of HIV infection in ways that might occur with HTLV-I. In this regard preliminary observations on the clinical status of patients dually infected with HIV and HTLV-II have suggested that there appears to be no difference in disease progression (86) and we have evidence that in some cases there may even be a slowing of the progression of HIV disease (unpublished).
In addition to the reports describing an association of HTLV-II infection with certain lymphoproliferative disorders, there is growing evidence that infection may also be associated with neurological disease. The first descriptions of such disorders were from two patients who were dually infected with HIV and HTLV-II and who presented with a myelopathy essentially indistinguishable from HAM/TSP (87,88). This was followed by a report that described two sisters singly infected with HTLV-II who developed a chronic neurodegenerative disorder characterized by spasticity, paraparesis, and ataxia and resembling an olivopontocerebellar atrophy variant of multiple-system atrophy (89). Although these individuals did have a component of spasticity, their disorder did not resemble classical HAM/TSP. The association of HTLV-II with neurological diseases was subsequently strengthened by two studies from Miami that described two and four females, respectively (90,91), all of whom had a distinctive presentation involving ataxia, spasticity, and variable alterations in mental status. Two additional reports (92,93) have also documented patients with HTLV-II infection who presented with symptoms identical to those of classical HAM/TSP. Taken together, these observations suggest that HTLV-II may be associated with a spectrum of neurological disorders ranging from spastic paraparesis/myelopathy with features typical of classical HAM/TSP to processes characterized by more widespread central nervous system involvement, where ataxia may be a prominent feature. It is interesting to note that all of the cases except one involving single HTLV-II infection involved females. This is similar to HAM/TSP, which also occurs more frequently in females. Interestingly, in those cases where the viruses have been analyzed by molecular methods, all were found to be infected with the HTLV-IIa subtype (91,93). While it would be premature to assume that this subtype has different pathogenic properties, these studies highlight the importance of investigating the properties of viruses in that a molecular correlate of pathogenicity may be eventually established.
HTLV-II infection is an ancient infection of American Indian populations where transmission is maintained primarily by breast-feeding and sexual activity. In recent times, the virus has been introduced into urban American, European, and Asian populations, in particular IVDAs, where it is, in addition, transmitted by contaminated blood products either following blood transfusion or by intravenous drug abuse activity. Although the role of the virus in human disease remains to be clearly established, there is accumulating evidence that infection may be associated with both neurological and lymphoproliferative disorders. Continued studies on the epidemiology of infection and the molecular and biological properties of the viruses, together with clinical and immunological evaluation of infected individuals, will yield important information on the pathogenicity of the virus and its role in human disease.
Acknowledgment: These studies were supported by Grant CA64038 from the NIH/NCI, General Clinical Research Center Grant M01-R0012 from the NIH, and the Japanese Foundation for AIDS Prevention.
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Proceedings of the VIIth International Conference on Human Retrovirology: HTLV