Introduction to the SV40 Genome, SV40 Early Proteins Large Tumor (T)-Antigen
and Small Tumor (t)-Antigen

tion enhancer element consisting of 72 base pair (bp) sequence repeats. The
early proteins synthesized are the two T-antigens, large T- and small t-antigen.
As the concentration of large T-antigen builds up in the nucleus, transcription
of the early genes is repressed by direct binding of the protein to the origin
region of the virus genome. After DNArepli-cation has occurred, transcription of
late genes occurs from the late pro¬moter and results in the production of the
structural proteins VP1, VP2, and VP3.
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Early in the 20th century endemic poliomyelitis gradually evolved into the
most devastating epidemic in the Western world. Striking improve¬ments in public
health, ironically, were accompanied by more frequent outbreaks of crippling
poliomyelitis. By 1950, each new day brought more polio victims, an increasing
sense of crisis, and a greater need for an effective therapy. In the United
States mass vaccination for paralytic polio began in 1955 with licensing of the
Salk inactivated vaccine. It is estimated that by 1960 90% of all persons under
20 years of age had received at least one inoculation; a total of 98 million
Americans had been immunized (1). A sharp decline in disease incidence occurred
and the spread of this crippling infection was abated.

competent natural hosts. The viruses typically reside in renal epithelial cells,
but can spread to other tissues and produce pathologic effects in either
immunocompromised hosts or, more importantly, in nonhost species (9).
Large-scale vaccine production in the United States neces¬sitated holding large
numbers of caged juvenile monkeys for tissue access, amplifying the probability
of transmission of SV40 from infected to nonimmune animals. The practice of
pooling kidney tissue from multiple animals during vaccine production increased
the likeli¬hood of viral contamination of vaccine cultures. It is now well
accepted that at least 30% and perhaps as much as 70% of inactivated live
vaccine produced between 1955 and 1961 was contaminated with SV40 (10). Although
the U.S. government established SV40-free vaccine manu¬facturing requirements in
1961, contaminated vaccine continued to be distributed through 1963.

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Historical Background

It was the Conference on the Biological Effects of Asbestos at the New York
Academy of Sciences, organized by Irving Selikoff in November 1964 (1), that put
both mesothelioma and asbestos on the map. Before that meeting, few people in
the scientific or general community had much knowledge of either subject. There
they learned the nature and numerous essential industrial uses of a group of
naturally occurring mineral fibers, collectively known as asbestos, although in
fact com¬prising at least five distinct materials, chemically, physically, and
geologically. Of these, chrysotile, a serpentine mineral mined mainly in Quebec
and the Ural mountains of Russia, made up over 90%. Of the remainder the two
most important were crocidolite and amosite, produced mainly in South Africa and
Australia, both amphibole min¬erals with distinctive qualities valuable for heat
insulation, naval marine use, and the production of large-bore cement pipes. Two
other amphibole mineral fibers were anthophyllite, of limited production in
Finland, and tremolite, little used, though by far the most widespread
geologically. Presenters at the conference stated that within some 20 years of
the first industrial exploitation of asbestos in the 1880s, workers heavily
exposed to airborne fiber and dust developed a dis¬tinctive, seriously disabling
and sometimes fatal diffuse pulmonary fibrosis, later termed asbestosis. Little
was done to limit exposure until the late 1930s, when after a well-conducted
survey of four asbestos textile plants in North Carolina, Dreessen et al (2) and
others of the U.S. Public Health Service recommended in 1938 that a workplace
dust con¬centration of 5 million particles per cubic foot (about 15 fibers/mL)
should not be exceeded. Mainly because of the Second World War, this
recommendation was not implemented; and probably for the same reason it went
unnoticed that there were case reports by some German pathologists (3) of
malignant tumors of the pleura and peritoneum in men with asbestosis. Thus it
was only in the 1950s that the causal asso¬ciation of asbestos exposure with
lung cancer in the United Kingdom (4), and later with mesothelioma in South
Africa (5), was recognized.

Until that time even the very existence of primary malignancies of the
mesotheleum was questioned by reputable pathologists. Looking back, however, a
review by Saccone and Coblenz (6) in 1943 had included the identification of
over 40 cases in autopsies published since 1870, and referred to two cases of
“endothelioma” reported in 1767 by Lieutaud in France among 3000 autopsies. That
mesothelial cancers in low frequency probably occurred well before the
industrial use of asbestos is discussed more fully later. Indeed, a low
background inci¬dence of unknown etiology has almost certainly continued,
affecting both children and adults.

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