Pergamon Leukemia Research Vol. 20, No. 6, pp. 457-458, 1996.

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COMMENTARY

HTLV INFECTION AND HEMATOLOGIC MALIGNANCIES

T. P. Loughran

Veterans Administration Medical Center, 800 Irving Avenue, Syracuse, NY 13210, U.S.A.

The first human retrovirus discovered, HTLV-I, belongs to a subgroup of retroviruses known as the primate T- cell lymphotrophic viruses (PTLV) [l]. This group of retroviruses also includes HTLV-II and simian T-cell leukemia viruses (STLV). Bovine leukemia virus (BLV) is structurally similar to PTLV. PTLV and BLV form an unusual genus of type-C retroviruses. This genus is characterized by a conserved epitope in their core proteins, which is absent from all other retroviruses. Also characteristic of this genus is a unique pX gene region, located between the env gene and the 3’ long terminal repeat (LTR). The pX gene encodes the Tax protein, which transactivates both viral and host genes. Upregulation of these viral and host genes is thought to play a critical role in disease pathogenesis [2].

The role of PTLV/BLV retroviral infection in causing hematological disease has not been fully defined. HTLV-I has been linked to adult T-cell leukemia (ATL) [3]. Since the discovery of a direct leukemogenic role for HTLV-I in ATL, HTLV-I infection has been recognized in association with hematological diseases other than ATL. Deleted or variant forms of HTLV-I have been detected in other T-cell malignancies, such as CD30+ lymphomas [4] and mycosis fungoides [5]. Mann and colleagues proposed an indirect role for HTLV-I in leukemogenesis by demonstrating antigen- committed B cells responding to HTLV-I in HTLV-I seropositive patients with B-CLL [6].

In contrast to HTLV-I, the pathogenicity of the antigenically related HTLV-II retrovirus is not as well established. However, a body of evidence continues to accumulate linking it to CDS+ T-cell malignancies, including some patients with LGL leukemia [7]. HTLV- II infection has not been established as an etiologic agent of any lymphoproliferative disorder, although the first two isolates (MO-T, NRA) came from patients with “atypical” T-cell hairy cell leukemia [8, 91. In retro- spect, it is not certain that T-cell hairy cell leukemia is a distinct entity. The clinicopathological features of hairy cell leukemia and LGL leukemia are similar, including neutropenia and splenic red pulp infiltration. Moreover, patient NRA had both a B-cell hairy cell leukemia and a CD8+ lymphoproliferative disorder. HTLV-II was

oligoclonally integrated only in the CD& cells [lo]. Patient NRA had many features of LGL leukemia (J. Rosenblatt, personal communication). BLV is the etiologic agent for chronic B-cell lymphocytosis and leukemia/lymphoma in cows. The disease induced by BLV is similar to HTLV-I-induced ATL, with a long latency period and lack of chronic viremia.

It is now well established that the genetic breadth of the HTLV/STLV strains is much greater than originally appreciated [ 111. Although the HTLV-I/STLV-I phylo- gram is complex, two major substrains have been defined. Cosmopolitan strains of HTLV-I (prototype: ATK) have low genetic variation (OS-3%) and have been identified from Japan, Africa, the Caribbean basin and the Americas. In contrast, highly divergent variants of HTLV-I, with only 92% sequence identity to cosmopolitan HTLV-I, have been isolated from remote populations of Papua New Guinea, the Solomon Islands, and from Australian aborigines [12]. There are two major subtypes of HTLV-II, with isolate MO-T being the prototype of HTLV-IIA [8], and the NRA isolate representing HTLV-IIB [9]. HTLV-IIB is endemic among Paleo-Amerindians [13]. Little data exist con- cerning BLV diversity. However, partial sequence analyses of seven isolates have identified only a 4% divergence to date.

Such analyses of genetic heterogeneity have led to some important conclusions: (1) the rate of mutation among the HTLV/STLV has remained relatively con- stant over time; and (2) a considerable amount of cross- species transmission has occurred even up until the recent past. These conclusions have two important implications. First, it is evident by examining the phylogenetic tree that diversity among PTLV-I is much greater than among the HTLV-II and BLV isolates [ 111. Given the equivalent rate of mutation, it is probable that more extensive analyses of primate and bovid samples should yield a more diverse phylogram for both HTLV- II and BLV. This hypothesis has been substantiated by the recent discovery of two novel forms of PTLV which are considerably divergent from both PTLV-I and PTLV-II [14,15]. Second, given the evidence for cross-species transmission, it is also reasonable to

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458 T. P. Loughran

assume that many other diverse PTLV/BLV variants will be discovered to have infected human populations around the world.

In this issue, Xu et al. describe some provocative findings suggesting a possible association of an HTLV- I-like retrovirus with acute myelogenous leukemia. Using an immunogold silver staining method with polyclonal HTLV-I positive human antiserum they demonstrated expression of HTLV-antigens on fresh and cultured AML cells. RT activity in such samples was shown using Poly A oligo dT as a template primer. Finally, immunoelectron microscopy appeared to show retroviral particles with type C morphology.

These preliminary findings are interesting but are not conclusive for infection with an exogenous HTLV-I-like retrovirus. It is known that certain human endogenous retroviruses may have cross-reactivity to HTLV-I antigens and demonstrate RT-like activity. False posi- tive RT activity can arise from mycoplasm infection (which may utilize Poly A oligo dT) or cellular DNA polymerase activity. Additional experiments with other template primers, such as poly C oligo dG would have been informative.

Experiments defining the relationship of the putative retrovirus to prototypical HTLV-I and HTLV-II would also be informative. The specificity of the observed reactivity of AML cells to polyclonal HTLV-I antiserum should be explored using a panel of well-defined monoclonal antibodies to HTLV-I and HTLV-II. DNA hybridization studies under low and high stringency should be performed to look for evidence of HTLV- related sequences in AML DNA. It would also be of interest to determine HTLV seroreactivity in these AML patients using newer recombinant Western blot assays which distinguish between HTLV-I and HTLV-II infection [16]. The seroreactivity pattern in such assays may also provide suggestive evidence of infection with HTLV-related retroviruses. For example, cross-reactiv- ity to HTLV-I gag p24 and env p21e has been observed in primates infected with novel forms of PTLV [14, 151. Experiments aimed at further characterizing the putative retrovirus are eagerly awaited.

References

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2. Sodroski J., Rosen C., Goh W. C. & Haseltine W. (1985) A transciptional activator protein encoded by the x-lor region of the human T-cell leukemia virus. Science 228, 1430.

3. Uchiyama T., Yodoi J., Sagawa K., Takatsuki K. & Uchino H. (1997) Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood 50, 481.

4. Anagnostopoulos I., Hummel M., Kaudewitz P., Herbst H., Braun-Falco 0. & Stein H. (1990) Detection of HTLV-I proviral sequences in CD30-positive large cell cutaneous T-cell lymphomas. Am. J. Pathol. 137, 1317.

5. Hall W. W., Liu C. R., Schneewind O., Takahashi H., Kaplan M. H., Roupe G. & Vahlne A. (1991) Deleted HTLV-I provirus in blood and cutaneous lesions of patients with mycosis fungoides. Science 253, 317.

6. Mann D. L., DeSantis P., Mark G., Pfeifer A., Newman M., Gibbs N., Popovic M., Sarngadharan M. G., Gallo R. C., Clark J. & Blattner W. (1987) HTLV-I-associated B-cell CLL: indirect role for retrovirus in leukemogenesis. Science 236, 1103.

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