Gene Regulation and Immunodeficiency 
B. Matija Peterlin, M.D. — Assistant Investigator 
Dr. Peterlin is also Associate Professor of Medicine and of Microbiology and Immunology at the University 
of California, San Francisco. He obtained his undergraduate degree in chemistry and physics at Duke 
University and his M.D. degree from Harvard Medical School. His postdoctoral work was performed with 
Jacob Maizel and Philip Leder at the NIH and with Hugh McDevitt at Stanford University. As a rheuma- 
tology fellow at Stanford, he chanced upon a family with the bare lymphocyte syndrome, which stimulated 
his research interest in this area. He is a member of the American Society for Clinical Investigation. 
SOME years ago we described a variant of the 
genetic disorder called the bare lymphocyte 
syndrome (BLS), in which the patient's lympho- 
cytes fail to express either class I, class II, or both 
major histocompatibility (MHC) determinants on 
their cell surfaces. These transplantation antigens 
are essential for the development of the immune 
system, for tumor surveillance, for eradication of 
viral infections, and for normal immune re- 
sponses. Thus it is not surprising that BLS patients 
are severely immunocompromised or fail to make 
antibodies or have autoimmune diseases. In addi- 
tion, this autosomal recessive syndrome is one of 
the two known inherited deficiencies of a regula- 
tory gene in humans. 
By fusing in tissue culture defective cells from 
different patients and those obtained by muta- 
genesis, four genetic complementation groups of 
BLS were found. The isolation of their defective 
genes should make possible prenatal diagnoses 
through use of specific genetic probes and might 
lead to the cure of BLS by the targeting of normal 
genes into the bone marrow of affected patients. 
To study the defective gene in BLS, we first ex- 
amined regions that regulate B cell-specific and 
interferon-7 (IFN-7) -inducible expression of 
class II genes. Next, we looked at proteins that 
bind to these DNA sequences and compared class 
Il-specific factors in various cell types. Distinct 
patterns of DNA-binding proteins were found in B 
cells, IFN-7-inducible cells, and T cells. 
We cloned several cDNAs encoding proteins 
that bind to B cell-specific and IFN-7-inducible 
sequences in class II promoters. One cDNA codes 
for JUN, which forms active JUN/FOS hetero- 
dimers in cells that do not express class II deter- 
minants. The remaining two cDNAs encode a B 
cell-specific helix-loop-helix protein, NF-IL6, 
and an ETS-like protein. By expressing one of 
these full-length cDNAs in human cells, we hope 
to rescue class II gene expression in one type of 
BLS. Besides direct biochemical studies, we are 
also using genetic approaches to rescue regula- 
tory defects in this disease. 
In setting up these genetic approaches, we first 
tested a well-known viral trans-regulatory system 
— namely, trans-activation of the human immuno- 
deficiency virus (HFV) by the virally encoded 
TAT protein. The precise mechanism of TAT ac- 
tion had not been defined. We discovered that 
TAT acts slightly downstream from the promoter 
to modify HIV transcription. Factors assembled 
near the site of initiation of HFV transcription 
bring the transcription complex to the promoter. 
The addition of TAT, which binds to an RNA stem- 
loop in the process of nascent transcription, re- 
leases this transcription complex, and efficient 
elongation of transcription and clearance of the 
promoter follow. New transcription complexes 
can then assemble, interact with TAT, and move 
quickly through the viral genome. Interactions 
between TAT, the RNA stem-loop, and cellular 
proteins have been defined. We hope that inter- 
fering with trans-activation by TAT will lead 
to new therapies for AIDS (acquired im- 
mune deficiency syndrome) and AIDS-related 
disorders. 
Since upstream promoter sequences are also 
essential for HFV replication, we clarified inter- 
actions between host cell factors and viral se- 
quences (long terminal repeat, LTR). Increased 
rates of initiation of HFV transcription were ob- 
served in activated T cells and macrophages. 
These result from actions of nuclear proteins that 
are also required for T cell and macrophage ef- 
fector functions and for T cell proliferation. 
Differences between LTRs of HFV types 1 and 2 
were observed that might explain the longer la- 
tency and attenuated clinical course of HIV-2 in- 
fection. Furthermore, effects of trans-activators 
encoded by several DNA viruses on HIV transcrip- 
tion were examined. Since effects of these ago- 
nists and TAT were synergistic, infection by DNA 
viruses might be an important cofactor in progres- 
sion from latent disease to clinical AIDS. 
Thus the quest to rescue the expression of class 
II MHC genes in a rare human congenital disease 
has led to genetic approaches to the study of tran- 
scription by RNA polymerase II and to the eluci- 
dation of a potent new transcriptional regulatory 
mechanism. 
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