Gene Regulation and Immunodeficiency 
B. Matija Peterlin, M.D. — Associate 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 
facob Maizel and Philip leder at NIH and with Hugh McDevitt at Stanford University. As a rheumatology 
fellow at Stanford, he chanced upon a family with the bare lymphocyte syndrome, which stimulated his 
interest in this genetic disorder. 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 determinants on their 
cell surfaces. These transplantation antigens are 
essential for the development of the immune sys- 
tem, 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, fail to make 
antibodies, or have autoimmune diseases. In ad- 
dition, this autosomal recessive syndrome is one 
of only two known inherited deficiencies of a reg- 
ulatory gene in humans. 
By fusing defective cells from different patients 
and those obtained by mutagenesis in tissue cul- 
ture, 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 possi- 
bly lead to the cure of BLS by the targeting of 
normal genes into the bone marrow of alfected 
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 that code for 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 heterodimers 
in cells that do not express class II determinants. 
Of the remaining two cDNAs, one codes for a B 
cell-specific helix-loop-helix protein and the 
other for an ETS-like protein. We are currently 
studying their genetic organization, expression, 
structure, and function. By expressing one of 
these full-length cDNAs in human cells, we hope 
to rescue class II gene expression in one type of 
BLS. In parallel with direct biochemical studies, 
we are also using genetic approaches to rescue 
regulatory defects in BLS. 
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 action had 
not been defined. We discovered that Tat acts 
slightly downstream from the promoter to modify 
HIV transcription so that efficient copying of the 
viral genome ensues. Factors assembled near the 
site of initiation of HIV transcription tether the 
transcription complex to the promoter. The addi- 
tion of Tat, which binds to an RNA stem-loop in 
the process of nascent transcription, releases this 
transcription complex. Efficient elongation of 
transcription and clearance of the promoter fol- 
low. New transcription complexes can then as- 
semble, interact with Tat, and move quickly 
through the viral genome. Interactions between 
Tat, the RNA stem-loop, and cellular proteins 
have been defined. For example, using a heterolo- 
gous RNA-tethering mechanism (that of the coat 
protein of bacteriophage Rl 7 that binds to its op- 
erator), we mapped activation and RNA-binding 
domains of Tat. By studying rodent cells and so- 
matic cell hybrids between rodent and human 
cells, we defined a cellular RNA-binding com- 
plex that facilitates interactions between Tat and 
TAR and is encoded on human chromosome 12. 
We hope that interfering with trans-activation by 
Tat will lead to new therapies for AIDS (acquired 
immune deficiency syndrome) and AIDS-related 
disorders. 
Since upstream promoter sequences are also 
essential for HIV replication, we clarified inter- 
actions between host cell factors and viral se- 
quences (long terminal repeat, LTR). Increased 
rates of initiation of HIV 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 HIV 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- 
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