Human Retroviral Gene Expression and 
Cellular Transcription 
Gary J. Nabel, M.D., Ph.D. — Associate Investigator 
Dr. Nabel is also Associate Professor of Internal Medicine and Biological Chemistry at the University of 
Michigan Medical School. He received his bachelor's degree from Harvard College and his Ph.D. and M.D. 
degrees from Harvard University. He was a research fellow at the Whitehead Institute, Massachusetts In- 
stitute of Technology, in the laboratory of David Baltimore. He then held a faculty position as an instruc- 
tor at Harvard Medical School before moving to the University of Michigan. 
T lymphocytes protect the body from invasion 
by foreign organisms, but can also become 
targets of infection by viruses. One of these is the 
human immunodeficiency virus (HIV), which 
causes the acquired immune deficiency syn- 
drome (AIDS). Under normal circumstances, T 
cells are activated in response to infection and 
begin to synthesize a set of proteins that step up 
the immunologic defense system. In T cells that 
contain HIV, cellular activation signals the virus 
to augment its replication. We have characterized 
regulatory proteins that stimulate gene expres- 
sion in T cells and retroviruses. These cells pro- 
vide a model for the study of coordinate gene 
expression during development and viral 
infection. 
Through the use of this model, we have identi- 
fied proteins that bind to control regions, regu- 
lating the expression of other immune system 
proteins and of HIV. We have also begun to use 
our knowledge of cellular and viral transcription 
to deliver recombinant genes in vivo. The T cell 
model has taught us more about the biology of 
these genes, and we have applied this knowledge 
to endothelial and vascular smooth muscle cells 
of the vessel wall, which has provided new oppor- 
tunities for therapeutic gene transfer. 
Regulation of HTV Gene Expression 
in T Cells and Monocytes 
HIV expression can be triggered in T cells by 
means of phorbol esters or other immune system 
activators. We have shown that stimulation of 
these cells increases the binding activity of a pro- 
tein called NF-/cB (nuclear factor that recognizes 
a sequence in the k immunoglobulin light chain 
of B cells) , which binds to a DNA control region. 
This factor stimulates HIV transcription in acti- 
vated T cells. The DNA sequence that NF-kB rec- 
ognizes is twice repeated in the HIV control re- 
gion, and mutation of these sites abolishes HIV 
inducibility. This transcription factor acts in syn- 
ergy with HIV products, such as the tat-l gene, 
further enhancing HIV gene expression in an in- 
fected cell. 
In addition to HIV type 1 (HIV-1), AIDS can be 
induced by a related virus, HIV type 2 (HrV-2) . A 
retrovirus, HIV- 2 shares nucleic acid and protein 
similarity with HIV-1. First described in West 
Africa, it has begun to appear throughout the 
world. The two viruses differ in the length of the 
asymptomatic period following infection. Be- 
cause progression of HlV-related disease is asso- 
ciated with increased viral replication, the rate of 
disease progression may be influenced by virus- 
activating regulatory proteins synthesized by host 
cells. 
Such proteins could themselves be regulated 
by distinct cofactors that selectively stimulate 
cellular activation pathways. These T cell activa- 
tion pathways regulate specific transcription fac- 
tors, which may contribute to the regulation of 
the latent phase of HIV infection. 
We have recently defined the transcriptional 
regulation and induction of these retroviruses 
and have found that the regulation of HIV- 2 
differs from that of HIV- 1 . A distinct T cell activa- 
tion pathway — triggering of the CD 3 component 
of the T cell antigen receptor complex — stimu- 
lates HIV- 2 gene expression but does not affect 
HIV-1. The response to T cell receptor stimula- 
tion in HIV- 2 is mediated by an upstream reg- 
ulatory element, CD3R, which is recognized 
by a sequence-specific DNA-binding protein, 
NF-CD3R. 
Jurkat T leukemia cell lines containing HrV-2 
provirus also showed increased viral replication 
following stimulation of the T cell receptor com- 
plex, in contrast to HIV- 1 . These findings suggest 
that transcriptional regulation and induction of 
HIV-2 differs from HIV-l. The studies also raise 
the possibility that different cofactors contribute 
to activation of disease associated with the two 
HIV types. 
Alteration of gene transcription by inhibition 
of specific transcriptional regulatory proteins 
would help to define how these factors partici- 
pate in cellular differentiation and viral infec- 
tion. Although several methods are known by 
which the functions of these proteins can be an- 
tagonized, each has specific limitations. Recently 
we have developed inhibitors of sequence- 
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