kidney. One initially isolated by others is involved 
in the genesis of the embryonic kidney neoplasm 
Wilms' tumor. In collaboration with Dr. Frank 
Rauscher's laboratory at the Wistar Institute, it has 
been shown that the product of this gene functions 
to shut down other genes. Two growth factor genes 
have been identified as targets. These data provide 
novel insights into how Wilms' tumors arise and im- 
prove our understanding of kidney development. 
Differentiated cells express unique sets of pro- 
teins that are located at different sites in the ge- 
nome. A major interest of the laboratory of Associate 
Investigator Gary J. Nabel, M.D., Ph.D. (University 
of Michigan) is to understand how cells regulate the 
expression of these diverse sets of genes during de- 
velopment and following viral infection. To address 
this question, the T lymphocytes that protect the 
body from invasion by foreign organisms have been 
analyzed. These cells are also the major target of 
infection by the human immunodeficiency virus 
(HIV), which causes the acquired immune defi- 
ciency syndrome (AIDS). In T cells that contain the 
AIDS virus, this activation process is used by HIV to 
activate viral replication, and Dr. Nabel's group has 
cloned and is characterizing one of the genes encod- 
ing a protein that binds to control regions regulating 
the expression of HIV and other immune system 
proteins. Knowledge derived from the study of such 
regulatory proteins has been used to deliver recom- 
binant genes into cells for further understanding 
and treatment of human diseases. 
Research in the laboratory of Assistant Investiga- 
tor Patrick O. Brown, M.D., Ph.D. (Stanford Univer- 
sity) has focused primarily on biochemical mecha- 
nisms in the replication of retroviruses, including 
HIV, the AIDS virus. Purification of integrase, the 
enzyme that mediates the introduction of retroviral 
genes into the host cell's DNA, has facilitated the 
group's efforts to understand this essential step in 
retroviral replication. Studies of the purified en- 
zyme are moving toward an understanding of the 
enzyme's structure and the mechanism by which it 
recognizes and recombines its two DNA substrates. 
In a separate area of investigation. Dr. Brown's 
group has recently developed a highly efficient new 
method for gene mapping, called genomic mis- 
match scanning. The method has been tested suc- 
cessfully using Baker's yeast as a test system. Current 
efforts are devoted to adapting the procedure so that 
it can be used to map genes that govern complex 
human traits. 
The pathogenic human retrovirus HIV- 1 (human 
immunodeficiency virus type I ) encodes two nu- 
clear regulatory proteins, Tat and Rev, that are es- 
sential for viral replication in culture. Both Tat and 
Rev are known to regulate viral gene expression 
through direct interactions with structured viral 
RNA target sites termed, respectively, TAR and RRE. 
Over the past year the laboratory of Associate Inves- 
tigator Bryan R. CuUen, Ph.D. (Duke University) has 
shown that the primary binding site for Rev on the 
RRE consists of as few as 13 nucleotides. Substitu- 
tion of this minimal Rev-binding site in place of the 
viral TAR element was shown to permit Tat function 
in the context of a Tat-Rev fusion protein but pre- 
cluded binding, and hence trans-activation, by wild- 
type Tat. Mutational analysis of both Tat and Rev in 
the context of this active fusion protein has facili- 
tated the identification of the specific biological 
roles of the different essential subdomains present 
in these viral trans-activators. This functional dis- 
section has clarified the mechanism of action of 
these critical HIV- 1 regulatory proteins and should 
facilitate the design of potential inhibitors. 
Research of Assistant Investigator Laimonis A. Lai- 
mins, Ph.D. (University of Chicago) and his col- 
leagues centers on the molecular biology of human 
papillomavirus (HPV) types 16, 18, and 31, which 
have been implicated as the causative agents of 
cancers of the anogenital tract. Transformation stud- 
ies in vitro have shown that both the E6 and E7 gene 
products are required for high-frequency transfor- 
mation of keratinocytes, as assayed by an ability to 
immortalize and alter differentiation of human epi- 
thelial cells. In a system where epithelial cells are 
grown at an air-to-liquid interface, HPV sequences 
have been shown to induce morphological changes 
similar to those seen in genital intraepithelial neo- 
plasias in vivo. Production of HPV has recently been 
induced from a continuous cell line concomitant 
with epithelial differentiation. Dr. Laimins and his 
colleagues have also examined in detail the tran- 
scriptional regulatory mechanisms utilized by papil- 
lomaviruses. One viral enhancer has been shown to 
be responsible for the tissue-specific expression of 
HPV genes and has been found to be regulated en- 
tirely by cellular factors. Factors controlling this en- 
hancer include members of the ubiquitous AP- 1 fam- 
ily, as well as a novel transcription factor, KRF-1. 
Competition between KRF-1 and Oct-1 for binding 
has been observed and may reflect a mechanism for 
repression of HPV expression. 
The research efforts in the laboratory of Assistant 
Investigator John B. Lowe, M.D. (University of Michi- 
gan) focus on understanding the function and regu- 
lation of specific mammalian cell surface carbohy- 
drate molecules and the glycosyltransferase genes 
that determine their expression. Several such genes 
have been isolated and characterized using systems 
developed in this laboratory. These genes and sys- 
GENETICS 141 
