Normal Human T Cell Growth, AIDS, and 
Adult T Cell Leukemia 
Warner C. Greene, M.D., Ph.D. — Investigator 
Dr. Greene is also Professor of Medicine at the Duke University Medical Center. He received his M.D. degree 
and Ph.D. degree in immunology from Washington University, St. Louis. After his internship and residency 
training in internal medicine at the Massachusetts General Hospital, Boston, Dr. Greene joined the 
Metabolism Branch of the National Cancer Institute at the NIH. Eight years later he was appointed to the 
staff at Duke. 
THE normal T cell immune response defends 
the host from many infectious organisms (vi- 
ruses, parasites, fungi, and bacteria) and elimi- 
nates cancer cells that may arise in the body. The 
catastrophic consequences of a defective T cell 
immune response are well illustrated by the ac- 
quired immune deficiency syndrome (AIDS), a 
fatal disease caused by infection of the helper 
subset of T lymphocytes with human immunode- 
ficiency virus 1 (HIV-1). 
Human T cell leukemia virus I (HTLV-I) also 
infects these helper T cells but, instead of pro- 
ducing T cell death, induces neoplastic transfor- 
mation leading to adult T cell leukemia (ATL). 
HTLV-I has also been recently linked with a pro- 
gressive demyelinating syndrome termed tropical 
spastic paraparesis, which resembles multiple 
sclerosis. This laboratory has focused its research 
efforts on further defining the biochemical pro- 
cesses that underlie both normal T cell growth 
and the abnormal patterns of proliferation that 
follow HIV-1 and HTLV-I retroviral infection. 
The cascade of biological events constituting 
the normal T cell immune response is normally 
triggered by the interaction of foreign antigens 
with antigen-specific receptor molecules arrayed 
on the surface of the resting T cell. Antigen bind- 
ing to these receptors in turn leads to T cell acti- 
vation and the expression of various growth- 
related genes, including those for interleukin-2 
(IL-2, T cell growth factor) and its high-affinity 
membrane receptor. The subsequent interaction 
of IL-2 with its receptor then promotes T cell pro- 
liferation, thereby increasing both the number 
and activity of the antigen-activated T cell clones. 
Structure and Function of the 
Interleukin-2 Receptor 
The functional IL-2 receptor corresponds to a 
membrane complex composed of two known li- 
gand-binding proteins, IL-2Ra and IL-2Rj8. In the 
absence of its counterpart, the a- and (8-subunits 
alone give rise only to low or intermediate recep- 
tor forms, respectively. The |8-subunit plays a 
dominant role in growth signal transduction, 
while the inducible expression of the a-subunit 
gene is centrally involved in the tightly regulated 
display of high-affinity forms of the IL-2 receptor. 
The IL-2R/3 gene is constitutively expressed in 
many resting T cells and natural killer cells. How- 
ever, immune activation of these cells promotes 
augmented IL-2R(8 expression. Recent studies 
have revealed the noncovalent association of two 
different kinds of protein kinases with the IL-2R|8 
subunit. Specifically, both a tyrosine kinase and a 
serine-threonine kinase interact with different 
segments of the intracytoplasmic domain of the 
IL-2R|8 receptor molecule. Studies are now under 
way to define the role played by kinases in growth 
signal transduction. 
Transcriptional Activation of HIV-1 
HFV- 1 may establish a latent or persistent form 
of infection within host CD4^ T cells and mono- 
cytes. Activation of these "latent" HIV-1 provi- 
ruses appears critically dependent upon select 
host transcription factors, including the NF-/cB 
family of proteins. These inducible factors bind 
to and activate the duplicated /cB enhancer ele- 
ment present in the HFV-l long terminal repeat 
(LTR). Recent studies indicate that as many as 
four different /cB-specific proteins are present in 
activated human T cells. Intriguingly, these four 
proteins are expressed in the nucleus with dis- 
tinctly biphasic kinetics (two early and two 
late), a process that involves both differences 
in the mobilization of preformed pools of these 
proteins and changes in the levels of gene 
expression. 
All four of these (cB-specific binding proteins are 
structurally related to the \-rel oncogene from the 
avian reticuloendotheliosis virus, REV-T. Remark- 
ably, wild-type but not nontransforming mutants 
of Y-rel specifically bind to the /cB enhancer and 
inhibit NF-kB function. These findings raise the 
possibility that v-re/-mediated cellular transforma- 
tion may be inextricably linked to its suppressive 
interaction with the kB enhancer. 
Trans-Regulation of HTLV-I Gene Expression 
Our recent studies of HTLV-I have focused on 
the critical function of the Tax and Rex trans- 
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