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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 275-282
Expression of the Human Immunodeficiency Virus-Tat Gene in Lymphoid
Tissues of Transgenic Mice Is Associated With B-Cell Lymphoma
By
Ramendra K. Kundu,
Frank Sangiorgi,
Lan-Ying Wu,
Paul K. Pattengale,
David R. Hinton,
Parkash S. Gill, and
Robert Maxson
From the Departments of Biochemistry and Molecular Biology,
Pathology, and Medicine, University of Southern California School of
Medicine, the USC/Norris Hospital and Research Institute, Los Angeles,
CA.
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ABSTRACT |
The human immunodeficiency virus type 1 (HIV-1) Tat gene, a potent
transactivator of viral and cellular genes, has been proposed as a key
agent in the pathogenesis of acquired immune deficiency syndrome
related disorders, including nonHodgkin's lymphoma. In cultured cells,
the HIV-1 Tat protein can induce the expression of the cytokines
interleukin-6 (IL-6) and IL-10, which are known to induce proliferation
and differentiation of lymphoid cells. Such alterations in cytokine
expression, together with a secondary genetic event, are thought to
ultimately lead to oncogenic transformation. To address the influence
of Tat on lymphoid development in the context of the whole organism, we
produced several transgenic mouse lines that express the Tat gene under
the control of an actin promoter. We show here that this promoter
directs expression to a variety of sites, including spleen, bone
marrow, and lymph nodes. Approximately 25% to 30% of the
Tat-transgenic population developed enlarged spleens within 1 year
after birth. On histological examination, a significant number of
spleens from Tat-transgenic mice exhibited malignant lymphoma of B-cell
origin. IgG heavy chain rearrangement confirmed the clonal B-cell
nature of these lymphoproliferations. In contrast, T-cell receptor
genes exhibited a germline (unrearranged) structure. Reverse
transcription polymerase chain reaction analysis of transgenic spleens
revealed that mRNA encoding cytokines IL-6 and IL-10 was upregulated,
suggesting a possible mechanism for the B-cell expansion in vivo.
© 1999 by The American Society of Hematology.
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INTRODUCTION |
HUMAN IMMUNODEFICIENCY virus type 1 (HIV-1) infection causes several clinical and immunological
abnormalities, including lymphadenopathy, activation of polyclonal B
cells, Kaposi's sarcoma, and nonHodgkin's lymphoma.1-2
Approximately 5% to 10% of acquired immune deficiency syndrome (AIDS)
patients develop such lymphomas, which are almost invariably derived
from B cells.3 Although the pathogenesis of AIDS-related
lymphoma is poorly understood, experiments in cell culture models have
shown that the HIV-1 Tat gene can cause changes in cytokine levels,
which, in turn, stimulate the growth of lymphoid cells.4
The Tat gene encodes a transregulatory protein with important functions
in the expression of HIV-1 genes.5 Tat is required for
efficient viral gene expression6 and functions by enhancing transcription elongation through interactions with the cis-acting transactivation response element (TAR).7,8 An interaction between Tat and cyclin T, a novel C-type cyclin, enhances the affinity
and specificity of the Tat-TAR interaction.8 Tat can also
interact with a region of the HIV-1 promoter that binds
AP-1/NF- B.9 Cotransfection studies have shown that the
Tat gene product can activate a number of cellular genes including
interleukin-6 (IL-6), which is known to stimulate lymphoid
development.10-12
Transgenic approaches have been used to address the function of Tat.
Transgenic mice carrying both the BK virus early region and the HIV-1
Tat gene develop a variety of neoplasms, including B-cell
lymphoma,13 although interpretation of these findings is
complicated by the coexpression of BK T-antigen together with Tat.
Expression of Tat under the control of the HIV-1 long terminal repeat
(LTR) causes skin lesions that resemble Kaposi's
sarcoma.14 Lymphoid hyperplasia results from the expression
of Tat directed by the cellular proteolipoprotein
promoter.15 Intriguingly, targeted inactivation of the IL-6
gene reduces susceptibility to B-lineage neoplasms
(plasmacytomas),16 consistent with the view that IL-6 may
function in the Tat pathway or parallel with Tat to modulate lymphoid development.
Findings that Tat is sufficient to cause at least some of the features
of AIDS, and that it may do so by affecting cytokine gene expression
raise the possibility that expression of Tat in lymphoid cells may be a
precipitating event in the development of nonHodgkin's lymphoma. In an
effort to develop an animal model that will provide a direct approach
to this issue, we created transgenic mice in which HIV-1 Tat is
expressed under the control of a chicken  -actin promoter. We show
that Tat is expressed in lymphoid cells of such -actin-Tat mice. We
show that -actin-Tat mice exhibit B-cell hyperplasia and clonal
rearrangement of Ig heavy chain genes, consistent with B-cell lymphoma.
Finally, we show that IL-6 and IL-10 mRNA levels are elevated in
spleens of -actin-Tat transgenic mice, suggesting that a Tat effect
on cytokine gene expression may contribute to lymphomagenesis.
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MATERIALS AND METHODS |
Generation of -actin/Tat-transgenic mice.
A 0.34-kb SalI-SalI chicken -actin promoter fragment
from the plasmid PUC -actin17 was first subcloned in
pSP73 (Promega, Madison, WI) vector. The vector was previously modified
with two NotI sites by inserting linkers at the PvuII
and EcoRV sites. A 300-bp BglII-SalI fragment
of Tat cDNA from pSVTat18 was subcloned into the
SmaI site of the pSP73 -actin plasmid. The 3.8-kb pSVTat plasmid was a kind gift from Dr B.M. Peterlin (UCSF, San Francisco, CA). A 2.5-kb fragment containing SV40 intron and poly A addition site
was excised from pKSV10 vector (Pharmacia, Piscataway, NJ) and inserted
downstream of the Tat cDNA to make the final plasmid. To generate
transgenic mice, a 3.14-kb NotI-NotI fragment
containing the full transcriptional unit was purified by CsCl density
gradient and microinjected into fertilized eggs from superovulated
B6CBA F1 females (Jackson Laboratories, Bar Harbor, ME)
previously mated to C57BL/6 males (Jackson Laboratories) as
described.19 Zygotes were implanted into B6CBA
F1 foster females. Founder transgenic animals were crossed
with C57BL/6 mice to generate stable transgenic lines. Additional
breedings were performed in each line to generate mice homozygous for
the Tat transgene.
Screening of transgenic mice.
The -actin-Tat transgene was detected in the founders and their
offspring by Southern blot.20 Ten micrograms of mouse
genomic tail DNA was digested overnight at 37°C with KpnI
(which cuts once in the transgene construct), electrophoresed in a
0.7% agarose gel, and transferred to a Hybond-N nylon membrane
(Amersham, Arlington Heights, IL) overnight. Hybridization was
performed in a solution containing 6X SSC (1X SSC: 150 mmol/L NaCl, 15 mmol/L Na-Citrate), 5× Denhardt's solution (1 mg/mL
polyvinylpyrrolidone, 1 mg/mL bovine serum albumin and 1 mg/mL Ficoll),
0.5% sodium dodecyl sulfate (SDS), 100 µg/mL salmon sperm DNA and
32P-labeled Tat cDNA at 68°C overnight. The filters were
washed once in 2× SSC/0.1% SDS at room temperature for 15 minutes,
once in 0.1× SSC and 0.1% SDS at 68°C for 30 minutes, and exposed
to Kodak X-OMAT films (Eastman-Kodak, Rochester, NY).
Isolation of subsets of B cells and T cells.
Spleens from normal and transgenic mice were harvested for isolation of
B cells, monocytes, CD4 and CD8 T cells by flow cytometry. One million
cells were labeled with either fluorescein isothiocyanate (FITC)-conjugated antibody to CD4 (Pharmingen, San Diego, CA) or
phycoerythrin-conjugated antibody to CD8 (Pharmingen) followed by
labeling with biotinylated secondary antibody anti-CD25 (Pharmingen) and phycoerythrin-FITC conjugated streptavidin (R & D Systems, Minneapolis, MN).
Northern analysis of Tat mRNA.
Total RNA was extracted from different tissues by the acid
guanidinium/phenol-chloroform method.21 Twenty micrograms
of total RNA of each sample was electrophoresed on a 1%
agarose-formaldehyde gel and blotted onto a Hybond-N nylon membrane
(Amersham). Hybridization was performed with Quikhyb rapid
hybridization solution (Stratagene, La Jolla, CA) containing 100 µg/mL of salmon sperm DNA and 106 cpm/mL of
32P-labeled 340-bp Tat cDNA fragment at 65°C for 2 hours.
Membranes were washed twice for 15 minutes at room temperature with
2× SSC/0.1% SDS and once for 30 minutes at 60°C with 0.1×
SSC/0.1% SDS. Signals were detected with Kodak X-OMAT film. The mouse
GAPDH and -actin cDNA were used as probes to control the amount of
RNA present in the gel.
Histological analysis.
Transgenic and control animals were anesthetized and sacrificed and
spleens were perfused with phosphate buffered saline. Spleens were
later fixed in formalin or B5 fixative and embedded in paraffin.
Sections (5 µm) were stained with hematoxylin and eosin.
Immunocytochemistry.
A mouse monoclonal anti-Tat antibody was purchased from ABL
(American Bio-technologies Inc, Cambridge, MA). The processing of
the tissue section and staining with the anti-Tat antibody were
performed with a kit obtained from Zymed Laboratories (San Francisco,
CA) according to the supplier's instructions. Antigen retrieval was
performed with methods previously described.22
Ig gene heavy chain rearrangement study.
Spleen DNA was extracted from control and transgenic
mice.21 The IgJ heavy chain probe and T-cell receptor
(TCR) probe were obtained from the plasmids p2-123
and p86T5,24 which were kind gifts from Dr Huang Fan
(University of California, Irvine, CA). Genomic DNA was digested
with EcoRI for JH and with HpaI for
analysis of TCR-. The hybridization and washing conditions for
these two probes were identical to those described in Screening of
Transgenic Mice.
Cytokine mRNA analysis by reverse transcription-polymerase chain
reaction (RT-PCR).
A range of dilutions of total RNA (1 to 5 µg) from splenocytes of
normal and transgenic mice was reverse transcribed with the cDNA
cycle kit (Invitrogen, Carlsbad, CA). An equal amount of cDNA product
from the reaction mixes was amplified with forward and reverse primers
for IL-6, IL-10, and GAPDH mRNAs. PCR primers used for the different
cDNAs were as follows: IL-6 forward, 5' TTC CAT CCA GTT GCC TTC TTG
G-3'; IL-6 reverse, 5' CTT CAT GTA CTC CAG GTA G-3'; IL-10 forward, 5'
GGA CAA CAT ACT GCT AAC CGA CTC 3'; IL-10 reverse, 5' AAA ATC ACT CTT
CAC CTG CTC CAC TT3'(24); GAPDH forward, GAA TCT ACT GGC GTC TTC
ACC 3'; and GAPDH reverse, 5' GTC ATG AGC CCT TCC ACG ATG C 3'. PCR
programs were 2 minutes at 94°C followed by 1 minute at 94°C, 1.5 minutes at 50°C (IL-6), 55°C (IL-10), and 56°C (GAPDH), and 1 minute at 72°C for 21 to 30 cycles with a final extension of the PCR
products for 10 minutes at 72°C.
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RESULTS |
Creation of HIV Tat transgenic mouse lines.
As a first approach to Tat function in a mouse model, we sought to
express Tat at moderate to high levels in a variety of tissue types,
including the components of the lymphoid system. We used the chicken
-actin promoter, which seemed likely to have the requisite
expression properties.17 This promoter was fused with a
full-length Tat cDNA sequence and a SV40 3' UTR and polyadenylation sequence (Fig 1). The transgene construct
was used to create three transgenic founder mice, which were bred into
a C57Bl/6 background to generate stable lines. Southern blot analysis
of DNA of each of these lines revealed multiple copies of the Tat
transgene integrated at a single site and oriented in a head to tail
tandem array (data not shown). The lines were designated 21, 24, and
29.
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| Fig 1.
Schematic diagram showing the structure of the
-actin-Tat transgene. The Tat cDNA was placed under the
transcriptional control of the chicken -actin promoter.
Transcriptional splicing and termination functions were provided by an
SV40-derived 3' UTR and polyadenylation signal. ( ), Chicken
-actin promoter; ( ), Tat cDNA.
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The Tat transgene is expressed in lymphoid tissues.
We examined Tat expression in lines 21 and 29 by Northern blot
analysis. Tat transcripts of the expected size were evident in several
tissues, including spleen and thymus (Fig
2A). Immunostaining of transgenic spleen
tissue with an anti-Tat antibody showed widespread expression of the
Tat protein (Fig 2C). To identify more specifically the lymphoid cell
types in which the Tat transgene was expressed, we fractionated
lymphoid cells into T, B, and monocyte compartments. Northern analysis
of RNA derived from sorted cells showed that T cells, B cells, and
monocytes contained Tat transcripts in readily detectable amounts (Fig
2B).
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| Fig 2.
Expression of HIV Tat mRNA and protein in tissues of
transgenic mice. (A) Northern blot analysis Tat mRNA in two independent
transgenic lines, 21 and 29. Whole-cell RNA was extracted from spleen,
thymus, and other tissues. The RNA samples (20 µg per lane) were
size-separated, blotted onto a membrane, and incubated with
radiolabeled Tat cDNA probe and, subsequently, with a -actin cDNA
probe. The blot was washed and exposed to x-ray film. (B) Expression of
Tat mRNA in lymphoid cells. Lymphocytes were sorted into T-cell and
B-cell components, from which total RNA was prepared, size separated,
and blotted. A mouse GAPDH cDNA probe was used as an internal control.
Sp, spleen; Th, thymus; CD4, CD4-positive T cell; CD8, CD8-positive T
cell; B, B cell; M, monocyte. (C) Immunodetection of Tat in histologic
sections of transgenic spleens. Spleens of Tat transgenic animals and
littermate controls were processed for histology, sectioned, and the
sections incubated with an anti-Tat monoclonal antibody. The
specificity of this antibody for Tat was documented
previously.33 The secondary antibody was a horseradish
peroxidase-streptavidin conjugate (×25).
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The Tat transgene causes lymphoproliferative anomalies, including
B-cell lymphoma.
We examined the brain, heart, liver, lung, spleen, and testis of Tat
transgenic and control mice. All tissues appeared normal except the
spleen. Tat transgenic mice (20 of 80 mice, representing three
independent lines) developed enlarged spleens between 12 and 15 months of age (Table 1). These spleens
weighed an average of 2.5 times the weight of a normal spleen.
Control mice, which were either littermates of Tat transgenics or
age-matched controls identical to the transgenics in strain background,
did not have enlarged spleens.19 Histological examination
of spleens of HIV-Tat-transgenic mice showed several
histopathologic differences relative to controls. There was an
increase in the size of white-pulp nodules as well as fusion of
adjacent lymphoid nodules in a substantial percentage of mice (Fig
3A and B).
Higher magnification of the nodules (Fig 3C) showed malignant
follicular center cell lymphomas composed predominantly of
irregularly shaped small lymphoid cells with a few larger follicular
center cells. This contrasted with the spleen histology reported by
Vellutini et al15 in transgenic mice bearing the Tat
transgene under the control of proteolipoprotein promoter. In these
mice, the red pulp showed extramedullary hematopoiesis with varying
degrees of hyperplasia of erythroid, myeloid, and megakaryocytic
precursors.
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| Fig 3.
Histological analysis of spleens of Tat-transgenic and
control mice. Tat-transgenic mice (lines 21 and 29) and littermate
control mice were killed at 12 to 15 months of age. Spleens were
removed and processed for histology. Shown are the representative
hematoxylin/eosin stains of (A) a control spleen (10×), (B) a
Tat-transgenic spleen (10×), (C) a Tat-transgenic spleen at high
magnification (25×).
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To confirm the involvement of B cells and to determine whether the
B-cell expansion was clonal, we tested for the rearrangement of Ig
heavy chain genes in the affected spleens of -actin-Tat transgenic
mice. Southern blot analysis with a JH heavy-chain probe
showed that such rearrangements did occur in a significant fraction of
Tat transgenic mice. Several examples are shown in Fig
4A. The data are summarized in Table
2. In addition to the germ line DNA
fragment of 6.6 kb, fragments of sizes ranging from 2.2 to 3.1 kb were
evident, indicative of a heavy chain rearrangement (Fig 4A). The
TCR- gene was not rearranged, ruling out a substantial clonal
expansion of T cells (Fig 4B). JH rearrangements were
detected in 8 of 40 total animals representing three independent
transgenic lines. No such rearrangements were observed in control
animals (Table 2). Because B-cell expansion was observed in three
independent transgenic lines, it could not have been a consequence of
an insertional mutagenesis event. Thus, our data show that
overexpression of the HIV-Tat gene is sufficient to cause B-cell
lymphoma.
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| Fig 4.
Southern blot showing Ig heavy-chain rearrangement in
splenic DNA of Tat-transgenic mice. DNA was extracted from spleens of
two independent lines of Tat-transgenic mice, 24 and 29. The DNA was
digested with EcoRI for IgJ heavy-chain analysis or
HpaI for TCR- analysis, blotted, and hybridized with an (A)
IgJ heavy-chain probe or (B) TCR- probe. C, control mouse; T,
Tat-transgenic mouse. C1-C3 and T1-T3 refer to individual control and
transgenic mice. Transgenic lines from which the mice were derived are
indicated above the blots. The sizes of the bands in kilobase are
indicated on the left. The 2.2-kb, 2.5-kb, and 3.1-kb bands in the
Tat-transgenic samples indicate a JH rearrangement; there
was no apparent rearrangement of the TCR- gene.
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Levels of IL-6 and IL-10 transcripts are elevated in spleens of
Tat-transgenic mice.
A number of studies have shown that Tat regulates the IL-6 and IL-10
genes.11,25-26 Transcripts of these genes are elevated in
lymphoid tissues of HIV-1-infected patients,16,27 and
cotransfection assays have shown that Tat can transactivate these genes
in cultured lymphoid cells.10 As an initial test of the
hypothesis that the Tat effect on B cells in Tat-transgenic mice is
mediated through IL-6, IL-10, or both, we performed a semiquantitative
RT-PCR analysis on RNA from transgenic spleens. Primers specific for
IL-6 or IL-10 were used against reverse-transcribed RNA from transgenic
and control spleens. Both the amount of input RNA and the number of PCR
cycles were varied to identify conditions under which the RT-PCR signal
was quantitatively related to the amount of input RNA (Fig
5). PCR
amplification of GAPDH sequences provided an internal control. As can
be seen in Figs 5A and B, the amounts of GAPDH PCR products were
similar in RNA samples from control versus Tat-transgenic mice. The
amount of IL-6 PCR product was substantially elevated in samples
derived from Tat-transgenic mice compared with controls. This elevation
was evident at several different PCR cycles and at three different
levels of input RNA: 1, 2, and 5 µg. Analysis of IL-10 mRNA yielded
similar results. Levels of IL-10 PCR product were substantially higher
in samples from Tat-transgenic mice compared with nontransgenic
controls. Comparison of the relative amounts of PCR products in Tat
transgenic versus control samples showed increases of approximately
threefold for IL-6 and fourfold for IL-10. We conclude that IL-6 and
IL-10 mRNA levels are substantially higher in splenic tissues of
Tat-transgenic mice compared with littermate or age-matched controls,
which is consistent with the view that the HIV-Tat gene may affect B
cells through the cytokines IL-6 and IL-10.
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| Fig 5.
RT-PCR detection of IL-6 and IL-10 mRNA in spleens of
Tat-transgenic mice. Whole-cell RNA from the spleens of age-matched
control and -actin-Tat-transgenic mice was reverse transcribed and
subjected to PCR using primers specific for IL-6 mRNA (A through C),
IL-10 mRNA (D through F), and GAPDH mRNA (internal control; A through
F). RT-PCR was performed with 1 µg of input RNA (A and D), 2 µg (B
and E), and 5 µg (C and F). PCR products were size-separated and
visualized by staining with ethidium bromide. Stained gels were
photographed and the PCR products quantitated by scanning with a laser
densitometer. M, 100-bp ladder. The areas of the IL-6 (A through C),
IL-10 (D through F), and GAPDH (control) peaks are plotted against PCR
cycle number. IL-6 Tat, measurement of IL-6 mRNA in Tat-transgenic
mice. IL-6 Con, measurement of IL-6 mRNA in control mice. IL-10 Tat,
measurement of IL-10 mRNA in Tat-transgenic mice. IL-10 Con,
measurement of IL-10 mRNA in control mice. Open circles, GAPDH in
Tat-transgenic mice; Open squares, GAPDH in control mice; The analyses
of IL-6, IL-10, and GAPDH were performed at the same time on the same
splenic RNA samples. The analyses shown in (A) and (B) were performed
on Tat-transgenic line 29. Parallel experiments conducted on line 21 yielded similar results.
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DISCUSSION |
We provide evidence that expression of the HIV-Tat gene in lymphoid
tissues is associated with the development of B-cell lymphoma in
transgenic mice. With a chicken -actin promoter to drive a Tat
transgene, we show that Tat mRNA is expressed in B cells, T cells, and
monocytes. We document in these -actin-Tat-transgenic mice several
morphologic and molecular features characteristic of follicular center
cell-derived B-cell lymphoma. These mice had grossly enlarged spleens,
which on histologic analysis exhibited an increase in the size and
number of white-pulp nodules. These nodules contained monomorphic
populations of small lymphoid cells primarily with irregular nuclei.
Southern blot analysis performed on DNA from transgenic spleens
revealed rearranged Ig heavy chain genes in approximately 20% of
transgenic mice, but did not show evidence of rearrangements in TCR
gene. Therefore, our data show a clonal expansion of B cells and not T
cells. Such rearrangements were not observed in age-matched control
mice and were, thus, specifically associated with the Tat transgene.
Splenomegaly and other features of lymphoma appeared in
-actin-Tat-transgenic mice between 12 and 15 months after birth. Because control mice did not develop lymphomas within this same time
frame, we can conclude that the Tat transgene plays a causative role in
lymphomagenesis. The Tat-transgenic mice are in a C57Bl/6 background,
which has a moderate incidence of lymphoma in older animals (39% of
animals aged 30 months or more for both males and
females).28 Thus, C57Bl/6 may provide a permissive genetic background for the development of Tat-induced lymphomas.
Transgenic approaches have implicated Tat in the development of
lymphoproliferative anomalies. Corallini et al13
reported B-cell lymphomas in transgenic mice expressing both the
HIV-1-Tat gene and the BKV T-antigen under the control of a BKV
promoter. However, because the BKV T-antigen gene was coexpressed with
Tat, it was not possible to determine whether Tat was sufficient to cause B-cell lymphoma. The use of the cellular lipoprotein
promoter to drive Tat expression produced mice with lymphoid
hyperplasia.15 In addition to these effects on lymphoid
tissues, expression of Tat under the control of the HIV LTR resulted
in skin lesions that resembled Kaposi's sarcoma.14
Our data extend these observations by showing that Tat is sufficient to
cause B-cell lymphoma when expressed under the control of the chicken
-actin promoter. It remains unclear why B-cell lymphomas were not
observed when Tat expression was driven by the cellular lipoprotein
promoter or the HIV-1 LTR. The relative strength of these promoters in
lymphoid tissues is one likely possibility, although direct
quantitative comparisons are lacking. Wei et al8 have shown
that cyclin T has a central role in the Tat:TAR interaction and that
overexpression of human cyclin T in NIH 3T3 and CHO cells significantly
enhances Tat activity in vivo. Species differences in the activity of
cyclin T may, thus, explain the inability of HIV to replicate in murine
cells. It is unclear whether cyclin T plays any part in the lymphoid
phenotypes exhibited by Tat-transgenic mice. However, it is attractive
to speculate that the introduction of a human cyclin T into the
-actin-Tat-transgenic mice might enhance the frequency of lymphomas
and other Tat-induced phenotypes.
Our demonstration by semiquantitative RT-PCR that mRNAs encoding the
lymphokines IL-6 and IL-10 are upregulated in spleens of
-actin-Tat-transgenic mice is consistent with the results of
cotransfection experiments showing that Tat can activate both promoters.11,12 These findings, both in transgenic mice and in cultured cells, together with findings that IL-6 and IL-10 can
stimulate the proliferation of B-lineage cells,4 suggest that lymphomagenesis in Tat-transgenic mice may be a direct result of
Tat-mediated enhancement of IL-6 and IL-10 transcription. Under this model, elevated levels of IL-6 and IL-10 would lead first to
enhanced proliferation of B cells and, ultimately, after a secondary
genetic change, to neoplastic growth. The availability of mice
bearing null mutations in IL-616,29 or IL-10 will allow a direct test of the roles of IL-6 and IL-10 in lymphomagenesis in
Tat-transgenic mice.
To what extent do the Tat-transgenic mice provide a model of
AIDS-related lymphoma? Because hematopoiesis is
sufficiently different in mice and in humans, making histologic
comparisons of types of lymphomas may be problematic.30,31
The most common types of B-cell lymphoma in patients with AIDS are
either aggressive Burkitt's or immunoblastic cell types that arise
from B cells. This contrasts with the B-cell lymphoma of the
Tat-transgenic mice, which was composed predominantly of irregularly
shaped small lymphoid cells arising from follicular center cells. On
the other hand, the molecular cascade leading to lymphomagenesis may
have common features: the roles of IL-6 and IL-10 as modulators of B-cell proliferation and differentiation are likely to be conserved between mice and humans.26,27,32 Moreover, IL-6 and IL-10 are elevated in lymphoid cells of patients with AIDS-related
lymphoma16,27 similar to our findings in the Tat-transgenic
mice. There is reason to believe, therefore, that the effect of Tat on
B cells operates by a similar mechanism in Tat-transgenic mice and
humans. Our Tat transgenic mice may thus serve as a model with which to
dissect the molecular pathways of Tat function. In the long term, these mice may also provide a means to investigate therapeutic approaches to
HIV infection based on interference with Tat activity.
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ACKNOWLEDGMENT |
We thank Anna Perez for pronuclear injections and the late C. Nugyen
Huu for initiating the project.
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FOOTNOTES |
Submitted August 31, 1998; accepted March 2, 1999.
Supported by grants from the National Institute of Health (NIH) to
R.M. (HD 22416) and D.R.H. (PO1 NS 26991) and a University of
Southern California/Norris translational research grant to R.M.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Robert Maxson, PhD, Department of
Biochemistry and Molecular Biology, and USC/Norris Hospital and
Research Institute, 1441 Eastlake Ave, Los Angeles, CA 90089-9176;
e-mail: maxson{at}zygote.hsc.usc.edu.
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