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, his M.D. degree from 
Harvard Medical School, and his Ph.D. degree in cell and developmental biology from Harvard University. 
He was a research fellow at the Whitehead Institute, Massachusetts Institute of Technology, in the 
laboratory of David Baltimore, before moving to the University of Michigan. 
T lymphocytes protect the body from invasion 
by foreign organisms but can also serve as tar- 
gets of infection by viruses. One such agent is the 
human immunodeficiency virus (HIV), which 
causes the acquired immune deficiency syn- 
drome (AIDS). Under normal circumstances, T 
cells become activated in response to infection 
and begin to synthesize a set of proteins that acti- 
vate the immunologic defense system. In T cells 
that contain the AIDS virus, cellular activation 
provides a signal to HIV to stimulate viral replica- 
tion. Our laboratory has characterized regulatory 
proteins that stimulate T cell and retroviral gene 
expression. These cells provide a model to study 
coordinate gene expression during development 
and following viral infection. 
We have identified proteins that, in binding to 
control regions, regulate the expression of HIV 
and other immune system proteins. At the same 
time, we have begun to use our knowledge of 
cellular and viral transcription to deliver recom- 
binant genes in vivo. This system has allowed us 
to learn more about the biology of these genes, 
particularly in endothelial and vascular smooth 
muscle cells of the vessel wall, and has provided 
new opportunities for studies on gene transfer. 
Regulation of HIV Gene Expression 
in T Cells and Monocytes 
The expression of HIV can be activated in T 
cells treated with phorbol esters or other immune 
system activators. We have previously shown that 
stimulation of these cells increases the binding 
activity of a protein that binds to a DNA control 
region, called NF-kB (nuclear factor that recog- 
nizes a sequence in the k immunoglobulin light 
chain of B cells) . NF-kB is responsible for stimula- 
tion of HIV transcription in activated T cells. The 
DNA sequence recognized by this transcription 
factor is twice repeated in the HIV control region, 
and mutation of these sites abolishes inducibility 
of HIV. NF-kB acts in synergy with HIV products, 
such as the tat-\ gene, to enhance HIV gene ex- 
pression in an infected cell. 
The transcription factor NF-kB is a protein com- 
plex composed of a DNA-binding subunit and an 
associated transactivation protein (of relative mo- 
lecular masses 50 and 65 kDa, respectively). 
Both subunits have similarity with the rel onco- 
gene and the Drosophila maternal-effect gene 
dorsal. The 5 0-kDa DNA-binding subunit was pre- 
viously thought to be a unique protein, derived 
from the 105-kDa gene product (pi 05). We have 
recently reported the isolation of a cDNA that en- 
codes an alternative DNA-binding subunit of NF- 
kB. It is more similar to pi 05 NF-/cB than other 
family members and defines a new subset of rel- 
related genes. It is synthesized as a protein of 
about 100 kDa (pi 00) that is expressed in differ- 
ent cell types, contains cell cycle motifs, and like 
pi 05, must be processed to generate a 50-kDa 
form. 
A 49-kDa product (p49) can be generated inde- 
pendently from an alternatively spliced tran- 
script. It has specific /cB DNA-binding activity and 
can form heterodimers with other rel proteins. In 
contrast to the 50-kDa protein derived from 
pl05, p49 acts in synergy with p65 to stimulate 
the HIV enhancer in transiently transfected Jurkat 
cells. Thus p49/plOO NF-kB could be important 
in the regulation of HIV and other KB-containing 
genes. The above studies are supported in part by 
grants from the National Institutes of Health. 
In addition to HIV type 1 (HIV-1), a second 
related virus, HIV type 2 (HIV-2), can induce 
AIDS. HIV-2, a distinct retrovirus, shares nucleic 
acid and protein similarity with HIV-1. First de- 
scribed in West Africa, HIV-2 has begun to appear 
throughout the world. Although HIV-1 and -2 
both cause AIDS, the length of the asymptomatic 
period following infection differs for the two 
viruses. 
Because increased viral replication is asso- 
ciated with progression of HIV-related disease, 
the rate of disease progression may be influenced 
by host cell regulatory proteins that activate virus 
replication. Such proteins could be regulated by 
distinct cofactors that selectively stimulate cellu- 
lar activation pathways. These T cell activation 
pathways regulate specific transcription factors 
that may contribute to the regulation of the latent 
phase of HIV infection. 
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