NORMAL HUMAN T CELL GROWTH AND PATHOGENIC HUMAN RETROVIRUSES 
Warner C. Greene, M.D., Ph.D., Investigator 
Investigations in Dr. Greene's laboratory have fo- 
cused on four principal areas: 1) the structure and 
function of the human receptor for interleukin-2 
(IL-2, T cell growth factor), 2) transcriptional regu- 
lation of the IL-2 receptor-a (IL-2Ra) gene, 3) func- 
tion and mechanism of action of the tax and rex 
trans-regulatory genes of the type I human T cell 
leukemia virus (HTLV-I), and 4) regulation of type 1 
human immunodeficiency virus (HIV-1) gene ex- 
pression by various viral and cellular factors. 
I. Human High-Affinity IL-2 Receptor. 
The functional high-affinity IL-2 receptor is now 
known to comprise at least two different IL-2 -bind- 
ing subunits, IL-2Ra (p55, Tac) and IL-2RP 
(p 70/75). Coexpression of cDNAs for these two 
subunits leads to functional receptor display in 
lymphoid, but not in nonlymphoid, cells. These 
findings strongly suggest that yet additional struc- 
tural subunits are involved in high-affinity receptor 
assembly. Dr. Greene and his colleagues have re- 
cently prepared monoclonal antibodies that appear 
to react with a third component of this receptor 
complex, a 52 kDa IL-2R7 chain. IL-2R7is expressed 
in a broader array of cells than either IL-2Ra or 
IL-2Rp. Immunoprecipitates formed with the anti- 
IL-2R7 antibodies contain high levels of tyrosine 
kinase activity. Although it remains unknown 
whether IL-2R7 is the receptor-associated tyrosine 
kinase, recent studies indicate that this second mes- 
senger system is intimately involved in IL-2-induced 
growth signal transduction. 
II. Transcriptional Regulation of the IL-2Ra Gene. 
The prior studies of Dr. Greene and his col- 
leagues have shown that a kB enhancer element 
present in the 5 '-flanking region of the IL-2Rot gene 
contributes significantly to the inducible nature of 
IL-2Ra gene expression. Mitogens [phytohemag- 
glutinin (PHA), phorbol 12-myristate 13-acetate 
(PMA)], cytokines [tumor necrosis factor-a (TNF- 
a)], and the Tax protein of HTLV-I all induce the ex- 
pression of KB-specific proteins that interact with 
this IL-2Ra enhancer element. At least four poly- 
peptides of different sizes react with the IL-2Ra kB 
element, as assessed in DNA-protein crosslinking 
assays. A related kB enhancer is also present in the 
IL-2 gene that reacts with these same inducible 
trans-acting factors, albeit with lower affinity. The 
common action of these KB-specific factors is likely 
involved in the coordinate expression in T cells of 
this growth factor and growth factor receptor gene. 
Sequences positioned immediately upstream and 
downstream of the IL-2Ra kB enhancer also con- 
tribute to the overall regulation of IL-2Ra gene ex- 
pression. Specifically, a 5'-binding site for a 56 kDa 
constitutively expressed protein is required for 
PMA, but not Tax, induction of this transcription 
unit. In contrast, a CArG box and Spl site located 
immediately 3' of the kB element are needed for 
both PMA and Tax activation. Finally, an upstream 
negative regulatory element (NRE) has also been 
identified in IL-2Ra promoter that attenuates both 
basal and induced responses. This NRE specifically 
interacts with constitutively expressed 50 kDa pro- 
tein. This same 50 kDa factor binds to an NRE pres- 
ent in the HIV-1 long terminal repeat (LTR). Thus 
the IL-2Ra promoter and HIV-1 LTR are not only 
coregulated by the same set of positive host factors 
(e.g., NF-kB) but also may be subject to negative 
regulation by the same inhibitory cellular protein. 
III. HTLV-I Trans-Regulation: Action of the Tax and 
Rex Proteins. 
The pathogenic HTLV-I retrovirus has been etio- 
logically linked with the aggressive and often fatal 
adult T cell leukemia and with the progressive neu- 
rological syndrome tropical spastic paraparesis. 
HTLV-I encodes two trans-regulatory proteins. Tax 
and Rex, each of which is required for viral replica- 
tion. The 40 kDa Tax protein serves as a powerful 
trans-activator of the HTLV-I LTR and various cellu- 
lar genes involved in T cell growth. These cellular 
targets include the genes encoding IL-2 and IL-2Ra. 
Tax does not directly bind to DNA but indirectly ac- 
tivates these cellular genes, in part by inducing the 
expression of the KB-specific family of proteins. In 
contrast, Tax activation of the HTLV-I LTR involves 
yet a second set of cellular proteins, indicating that 
this viral trans-activator interfaces with multiple 
host transcription factor pathways. 
The HTLV-I Rex protein functions post-transcrip- 
tionally to regulate viral structural gene expression. 
Rex acts in part by inducing the nuclear export of 
the unspliced or singly spliced viral mRNAs that 
encode the structural proteins (Gag and Env) 
required for the assembly of infectious virions. In 
the absence of Rex these incompletely processed 
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