Molecular Biology of Human Papillomaviruses 
LaimonisA. Laimins, Ph.D. — Assistant Investigator 
Dr. Laimins is also Associate Professor of Molecular Genetics and Cell Biology at the University of Chicago. 
He received his Ph.D. degree in biophysics and theoretical biology from the University of Chicago. His 
postdoctoral research was done with George Khoury at the National Cancer Institute. 
MY laboratory is studying the molecular biol- 
ogy of human papillomaviruses types 16 
and 18. HPV- 1 6 and - 1 8 are the etiological agents 
of the many malignancies of the urogenital re- 
gion, and in particular those of the cervix. More 
than 70 different types of HPV are known to in- 
fect cutaneous and mucosal epithelia in various 
body locations. Some types induce warts on the 
hands or soles of the feet, but are never found in 
genital lesions. Similarly, the viruses that induce 
warts in the genital region are never found on the 
hands or feet. 
The majority of HPVs cause benign warts, and 
about one-third of the types are specific for geni- 
tal epithelium. A subset of these viruses (HPV- 16, 
-18, -31, and -51) infect the cervix and are 
strongly associated with the development of 
cervical cancer. Although the number of HPV- 
positive individuals has increased 10-fold in the 
last 10 years, effective monitoring procedures 
such as the PAP smear have limited the increase in 
cervical cancers in the United States and Europe; 
Up to 20 percent of the population in these 
countries is infected by some type of genital HPV, 
particularly the non-oncogenic types 6 and 1 1 . 
However, many cases of infection by HPV- 1 6 and 
-18 without visible lesions have been reported. It 
therefore appears that although infection by 
HPVs is necessary for the development of cervical 
cancer, infection alone is not sufficient to induce 
malignancy. In low-grade lesions, or condylomas, 
viral DNA is present in the cell as episomes, and 
progeny viruses are produced. In contrast, in cer- 
vical cancers the viral genome is found integrated 
into the host chromosome, and no viral particles 
are synthesized. One model for progression from 
a low-grade lesion to a cancer suggests that inte- 
gration is important in the development of the 
cancer and that it may act by the removal of a 
dominant inhibitor of transformation. Viral inte- 
gration into the chromosome may thus be the first 
step of a multistep carcinogenic process. My labo- 
ratory is currently studying the molecular mecha- 
nisms by which HPVs contribute to this process. 
A major impediment to the study of HPVs has 
been an inability to propagate these viruses in 
culture. Papillomaviruses are unusual in that 
their life cycle is tightly coupled to the differen- 
tiation program of epithelial cells. Although most 
viruses infect one cell type and undergo a produc- 
tive infection in the same cell, HPVs infect basal 
epithelial cells, establish their genomes as epi- 
somes, and only replicate upon cellular differen- 
tiation, with amplification of viral DNA and ex- 
pression of late genes. Inability to duplicate this 
differentiation process in vitro long prevented 
the successful propagation of virus. We have re- 
cently duplicated several features of these pro- 
ductive infections of HPV in culture, and current 
studies are directed at identifying how these dif- 
ferentiation-specific properties are controlled. 
This work is supported by a grant from the Ameri- 
can Cancer Society. 
My laboratory has found that HPV can immorta- 
lize epithelial cells derived from either human 
foreskin or cervix in tissue culture. Normally pri- 
mary cells have only a limited life span in vitro, 
but the presence of the HPV E7 protein is suffi- 
cient to allow for unlimited grov^h in culture. 
The loss of differentiation is usually a charac- 
teristic of many epithelial cancers, including 
those of the cervix. We have been studying how 
HPV viral proteins alter epithelial cell differen- 
tiation. In low-grade lesions in which infectious 
viruses are produced, these proteins only slightly 
alter epithelial differentiation. In cervical can- 
cers, on the other hand, infected cells have lost 
all ability to differentiate. 
We have also used a system that accurately mim- 
ics the differentiation properties of epithelial 
cells in vitro, to show that HPV sequences alter 
the ability of epithelial cells to differentiate. The 
morphological changes that are seen in this tissue 
culture system are very similar to those seen in 
low-grade cervical neoplasias. In tissue culture, 
our HPV cell lines quickly lose the ability to dif- 
ferentiate and develop the appearance of high- 
grade neoplasias or cancers. Two HPV genes, E6 
and E7, seem to be required for this transforma- 
tion process. We believe this loss of differentia- 
tion may be an in vitro model for the develop- 
ment of cervical cancer. In the future, we hope to 
utilize this model to identify other important fac- 
tors involved in controlling the development of 
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