The Human T-Cell Leukemia Virus Family, Adult T Cell Leukemia, and AIDS
 
R.C. Gallo, M. G. Sarngadharan, M. Popovic, J. Schupbach, P. Markham, S.Z. Salahuddin, G. Shaw, F. Wong-Staal and M. S. Reitz Jr 

 Laboratory of Tumor Cell Biology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, MD 20205,

USA Hämatol. Bluttransf. Vol 29

A. Introduction

Human T cell leukemia virus (HTL V) is the name by which we have designated a family of related retroviruses from humans, HTLV type I (HTLV-I) is the name we gave the first human retrovirus isolate, HTLV-I is endemic at low rates in different parts of the world, including southern Japan, the Caribbean, South and Central America, the southeastern United States, and especially in Africa, Seroepidemiologic studies show that HTL V-I is the primary etiologic agent of an aggressive form of adult T cell leukemia/lymphoma (ATLL), Infection with HTLV-I in vivo occurs preferentially with OKT4+ T cells and results in immortalization of the infected cells as well as abrogation of various immune functions of the infected cells, in keeping with its role in the etiology of ATLL, A second related but distinct virus, HTL V type II ( HTL V-II ), was identified by us in collaboration with D, Golde and colleagues after type I, in material from a patient with hairy cell leukemia, HTLV-II shares many features with HTLV-I, including in vitro transforming activity, but it has been isolated only rarely and has not yet been associated with any disease, A third virus, HTL V type III (HTL V-III), has been isolated many times from individuals who have acquired immunodeficiency syndrome (AlDS) or are at risk for this disease, HTLV-lII shares some antigenic cross-reactivity with land Il, as well as some general features, including an OKT4+ T cell tropism, The virus is more highly infectious than lor II, however, and has so far shown only cytopathic and not immortalizing effects, Seroepidemiologic data show that HTLV-lll is the cause of AIDS.

B. HTL V -I and Adult T CeII Leukemia/Lymphoma

The first human retrovirus isolates were obtained from malignant T cell lines established with the use of T cell growth factor (TCGF), a protein present in the media of peripheral blood cells stimulated with phytohemagglutinin [ l, 27, 40], The T cell lines were established from black patients in the United States with what were diagnosed as unusually aggressive variants of cutaneous T cell lymphoma [28, 29, 35], The virus, which we called HTLV-I, has typical retrovirus morphology ( Fig, l) and, like other retroviruses, contains both a reverse transcriptase and high-molecularweight polyadenylated genomic RNA, HTLV-l was shown to be unique by the criteria of protein serology [l4, 37, 38] and nucleic acid hybridization [35], and to be exogenous to man [35], Transmission is horizontal and does not occur genetically [9,54],
The isolation of HTL V-I made it possible to make antibodies to the viral proteins, These antibodies were then used to test serum sam pies for the presence of HTL V -I. Most persons in the Unitcd States were negative for this virus, including patients with many types of leukemia and lymphoma, HTLV-I was detected in a small fraction of persons from the United States with cutaneous T cell leukemia or lymphoma, most of whom were blacks in the southeastern United States or of Caribbean origin [4, 30]. Even most of these patients were negative.

Fig. 1. Electron microscopy of HTLV-I, II, and III. Shown are budding (panels a), immature (panels b),
and maturc (panels c) virions of the three types of HTL V. The bar in 3 b equals IOOnm


Two regions of the world were identificd, however, in which thcre were endemic discases which clinically resemblcd those from which the first two isolates ofHTLV-I werc obtained, These regions were the Caribbean [5] and southwestern Japan [51]. The disease in the Caribbean was called lymphosarcoma cell leukemia, and that in Japan was called adult T cell leukemia; both were found to be closely associated with the presence of HTLV-I by seroepidemiology [3, 13, 39]. Both diseases are now regarded as the same clinical entity, and are collectively called adult T cell leukemia/lymphoma (ATLL).
Similar results have been reported by investigators in Japan, who also isolated retroviruses from A TLL cell lines [25, 54]. These retroviruses are now known to be isolates of HL TV-I [52]. Sporadic occurrences of both HTLV-I and ATLL have been noted in many other areas of the world [ 10], and most recently parts of Africa have also been shown to be endemic [43].
As is true for the naturally occurring ani
mal leukemia viruses, only a small fraction of HRV-I-infected people develop leukemia [50]. It thus appears as though other factors, such as the host immune response, age at exposure, virus dose, or route of infection, may be important factors in determining the end result of infection.

Table I. Relatedness of HTLV-I, II, and III

C. In Vitro Biological Effects of HTL V -I

HTLV-I was first shown by Miyoshi et a]. to transform T cells [26], but the target cells were not shown to be initially free of virus. Subsequently, transformation was achieved using target T cells shown to be HTL V -I negative [31,32].
HTL V- I is tropic for T cells of the O KT4 + phenotype both in vivo [9] and in vitro [19, 31, 32]. Transmission is achieved easily by co-cultivation with killed virus-producing cells, but only with difficulty when cell-free virus is used. The infected cells take on many of the properties of transformed ATLL cells, including altered morphology, increased growth rate, the tendency to grow in clumps, reduced dependence on TCGF, expression of high levels of the TCGF receptor and HLA-Dr antigens on the cell surface, and (usually) immortalization in culture [22,23, 31, 32]. In vitro transformation by HTL V- I seems to be m uch more rapid and efficient than leukemogenesis in vitro.
Infection with HTLV-I of functional T cells results in the loss of some or all of their immune functions. For example, a T cell line which was cytotoxic for autologous tumor cells was established from one (rare) long-term survivor of ATLL [22]. These cells were themselves infectable with HTLV-I, and one clone ofinfected cells was shown to have lost the ability to kill its target cells. Instead, the cell would stop dividing and die when presented with the target [23]. Various other functional losses after infection with HTL V-I have been reported in addition [24, 34]. HTL V-I also infects bone marrow cells in vitro, giving rise to T cell lines of different phenotypes, including OKT4+T8-, OKT4-+, and OKT4-8-.

D. HTLV-II

HTL V-II was originally isolated from a patient with hairy cell leukemia [16]. Although it shares antigenic determinants of the major gag protein, p24, and the envelope proteins [16, 18] of HTLV-I, it is readily distinguishable by both protein serology [ 17] and nucleic acid hybridization [36]. It has many common biochemical properties with HTLV-I (see Table I), including the ability to transform T cells in vitro and to mediate a loss ofimmune functions [34]. It has been isolatcd only twice, and in spite of its biological activity in vitro it is not clear at this time with what disease, ifany, it is associated.


Fig.2. Genomes and rcstriction maps of HTL V-I and II. lamda MO15A is an example of HTLV-II, lamda 23-3 and lamda CH-1 are examples of HTLV-l, and lamda MC1 is HTLV-Ib. Genomic regions corresponding to L TR, gag, pol, env, and pX are drawn to scale according to the publishcd nucleotide sequence of an HTL V-I isolate. Two Bg1ll sites in thc 5' end of lamda MO 15A are not shown

E. Genomes of HTLV-I and HTLV-II

The genome of HTL V -I has been completely sequenced [45]. HTLV-I contains two large terminal repeat (L TR) sequences, in common with other retroviruses, which contain transcriptional control signals. There are fairly typical gag, pol, and env genes, although the gag gene seems to code for three proteins rather than four. In addition, there is an extensive stretch of DNA 3' to the env gene, which contains several potential open reading frames capable of coding for proteins. This is called the pX region, and does not seem to be necessary for viral replication. It may be important in cell transformation, as discussed below, but it is not a cell-derived onc gene, since it has no homology with host cell DNA, The structure of the HTLV-I genome is shown in Fig. 2.
The HTLV-II genome also contains a pX region, and has the same gene order as HTL V-I [46]. Heteroduplex analyses using relaxed hybridization conditions indicate that the two viruses are at least distantly related over the length of their genomes. The 3' portion of pX region seems to be the most closely conserved part of the genome. The HTLV-II pX has been recently sequenced [23], and the 3' part of this sequence has a large open reading frame which has the coding potential for a protein of at least 38 kilodaltons. The close homology with the analogous region of the HTLV-I genome suggests that the product for which these regions code is important for the biological activity of these viruses.
The env gene sequence of HTLV-II has also been recently reported [47], and it also shows significant homology with the HTLV-I env gene, except for the extreme 3' and 5' termini, The L TRs of the two viruses are markedly different over most of their length [49], but small regions near the RNA cap site, the primer binding site, and a 21base pair sequence present at four copies in the HTL V -II L TR and three copies in the HTL V-I L TR are highly homologous. These last sequences could represent RNA transcriptional enhancers.
How do HTL V-I and II transform T cells? One puzzling aspect of the molecular biology of HTLV-I and II is that although transformation of infected cells is rapid, the viral genome does not contain atypical (i,e" cell-derived) onc gene. Moreover,leukemogenesis appears to be relatively inefficient and to involve a long latent period, as with the chronic animal leukemia viruses.
A second puzzling feature of transformation is that the proviral integration site in fresh leukemic blood cells, leukemic cell lines, and cord blood T cell lines transformed in vitro is nearly always mono- or oligoclonal [23, 53-55], suggesting that only a few of the infected cells become transformed. There does not, however, seem to be a preferential integration site common to different leukemic patients or cell lines [53, 55], suggesting that a specific integration site is not required for transformation, and that the viral genome itself contains all the necessary information.
What is the reason for these apparent paradoxes? It has been shown that the activities of the HTLV-I and II RNA polymerase promoters are ,strongly intlucnccd by the cell type in which they are present [6, 48], and are far more active in T cells than in other cells. Activity is higher in cells already infected with HTL V than in uninfected cells. This has been interpreted as indicative of the presence of a trans-acting factor present in HTL V-infected cells, which strongly activates the HTL V promoter. Sodroski et al. [48] suggest that this factor may in fact be the pX product. If this were the case, and if it had the ability to af-fect the promoters of cellular genes necessary for T cell function and growth, it could help to explain both rapid transformation by HTLV without the requirement for a specific integration site and a cytopathic or dysfunctional effect on infected T cells. It does not explain, however, the monoclonality of transformed cell populations with respect to the viral integration site.

F. HTL V -III and AIDS

Acquired imm unodeflciency syndrome
(AIDS) is a recently recognized, generally fatal disease involving helper T cell depletion and multiple opportunistic infections and/or malignancies. It is prevalent among certain high-risk groups, including promiscuous homosexuals, intravenous drug abusers, hemophiliacs, Haitians, and in fants born to members of high-risk groups. Because epidemiologic data suggested involvement of a transmissible agent and because of the involvement of OKT4 + T cells in the disease, it seemed possible that an HTL V-Iike retrovirus might be involved. Essex et al. reported the presence of an antibody present in a large percentage of AIDS victims and high-risk populations which reacted against a cell surface protein ofHTLV-I-infected cells [7,8].
Recently, we reported on a cell line permissive for the growth of a retrovirus from AIDS and pre-AIDS patients [33]. More than 90 isolates from this group of viruses have been obtained [ 1]; P. Markham et al., in preparation]. Based on morphology, biochemical properties of reverse transcri ptase [33], antigenic determinants of env and gag proteins [44], and demonstration of distant but significant nucleic acid homology in the gag-pol region, this new virus is distantly related to HTLV-I and II, and has been designated HTLV-III. A more detailed characterization of HTL V-III is given by Wong-Staal et al. (this volume).
The distant relatedness of these viruses suggests that the antibody activity described by Essex and his colleagues retlected crossreactivity of HTLV-I antigen with antibodies to HTLV-III. We have isolated HTL V-III from a majority of pre-AIDS patients and a large number or actual AIDS patients [1]], but isolation from the normal population is rare. Almost all AIDS and pre-AIDS patients have antibodies to HTL V-III [42]. A typical Western blot is shown in Fig. 3. The major reactivity is against a 41K protein, which is probably the env antigen of HTLV-III. The most recent data show that the prevalence of such antibodies in these patients is virtually 100% [41]. The association is so striking as to overwhelmingly suggest that this virus is the cause of AIDS. Recent evidence indicates that the virus called ALV or IDAV, detected previously by Barre-Sinoussi et al. [2], is a member or the same HTLV subgroup.
These accumulated data indicate that there is a group of related human retroviruses with disparate effects on the same target cell, the OKT4+ T cell.

Fig.3. Analysis of sera for antibodies to HTL VIII by Western blot. A. Sera from AIDS patients; B sera from lymphadenopathy patients; C a positive and a negative serum from homosexual subjects. Numbers refer to the molecular weight in kilodaltons

It will be interesting to see whether there are other similar viruses that have yet to be discovered. The identification of the present members of this group gives us opportunities to study T cell biology, as well as the potential to intervene in certain now fatal (and at least in the case of AIDS, increasingly prevalent) T cell diseases.

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Fig.2. Hypothetic pathogenesis of Hodgkin's disease


undefined cell in normal tissue [ 13, 15], which could be the normal counterpart of the "malignant" H- and SR-cells (see Stein, this volume). The pathogenetic mechanisms involved in the transformation of a normal cell, possibly playing some role in immune and hematopoietic regulation, is unknown. Endogenous (genetic?) and exogenous (viruses, chemical agents, both?) might induce a gradual "evoIution" from a primarily nonproliferating, biologically active cell, which by its products (CSF, II 1) might create the clinically not very aggressive "Hodgkin's lymphoma ", to a genetically altered (Fonatsch et al. unpublished results) more malignant cell, embedded in the histological entity of a "Hodgkin sarcoma." Radiochemotherapy might act as a cofactor in this process of gradual malignization. Of the HD patients, however, 60%-90% are cured by radio- and/ or chemotherapy in the early stages of this process before genetically altered cells have chance to commence rapid proliferation and possibly exert resistance to cytoreductive therapy. The variance in the histological presentation of Hodgkin's disease could reflect this gradual malignization process: Paragranuloma and/ or lymphocytic predominance and lymphocyte-enriched nodular sclerosis would identify a stage of "low risk", with a high functional activity of the H- and SR-cells, producing mediators like CSF, Interleukin 1, but still restricted in cellular proliferation. If cytoreductive therapy is carried out at this stage, cure is possible in up to 90% of cases ([ 10], Schellong, personal communication). If the HD cells withstand therapy by either genetically inherent or resistance mechanisms acquired during treatment, the patient will present a picture of a more malignant Hodgkin's sarcoma with a higher number of rapidly proliferating H- and SR-cells. These cells could still have retained their biological mediator production, but the balance might be toward more production of immune suppressive and EBV transformation enhancing factor. The fact that many Hodgkin's disease patients develop high antibody serum titers against EBV antigens and give rise to EBVinduced lymphoblastoid cell cultures significantly more than normal individuals [4] could be explained not only by T -cell immunosuppression but also by a direct influence of an EBV transformation enhancing factor. The resulting polyclonal lymphoblastoid transformation could "feed" or protect the tumor cell, possibly under a concomitant protection of the rosetting OKT-4-positive T -helper cells, attaching to the H- and SR-cells. These protection mechanisms might enable an a priori "lowgrade malignant" HD cell to "sneak through" to a higher malignant proliferating tumor cell, which in 15%-20% of the clinical outcome could eventually kill the patient. Most Hodkgin's disease patients, however, do not die of tumor cell proliferation, but of biological side effects of immune deficiency and hematological complications, possibly due to some of the descri bed factors.


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