Ht
DEPARTMENT OF
BIOCHEMISTRY & BIOPHYSICS

   

Wa ANNUAL REPORT
My 1982 1983

UNIVERSITY OF CALIFORNIA SAN FRANCISCO
HAROLD E. VARMUS
Professor of Microbiology and Immunology

 

In this laboratory, we use two intriguing and medically-— important
classes of animal viruses~--the retroviruses and hepatitis B-type
viruses—~-as points of departure for studying various aspects of the
behaviour of eukaryotic cells at the molecular level. Several properties
of these viruses extend our concerns beyond the usual confines of virology:
the oncogenes of retroviruses are derived from normal cellular genes that
are themselves targets for mutations implicated in many types of cancers;
the DNA form of the retroviral genome (the provirus) is structurally
similar to transposable elements from all types of living organisms; RNA-
directed DNA synthesis is central to the life cycles of both classes of
virus and now appears to be a mechanism used in the molding of the
eukaryotic genome; the complex pathological consequences of persistant
infections by both virus classes involve a wide range of interactions
between viral and host macromolecules; and the regulation of viral gene
expression displays many features characteristic of cellular genes, but
more conveniently addressed with viral reagents.

I. RETROVIRUSES AS TRANSPOSABLE GENETIC ELEMENTS

A. The Mechanism of Proviral Integration

 

The central event in the retrovirus life cycle is the covalent inte-
gration of a DNA copy of the RNA genome into host chromosomes. Although
a great deal is known about the synthesis of unintegrated double stranded
viral DNA by the virus-coded enzyme, reverse transcriptase, we know only
the structure features of integrated (proviral) DNA and none of the
functional properties of the integrative mechanism. Like many transposable
elements from plants, bacteria, yeast, and insects, proviruses can be found
at many different sites in host genomes but are always joined to host DNA
at the same sites in viral DNA. The provirus contains viral genes arranged
as they are in viral RNA (most commonly: 5'~gag-pol-env-3'), flanked by long
terminal repeats (LTRs) that are generated during reverse transcription and
used for regulation of transcription. The LTRs terminate with short inverted
repeats, and the entire provirus is flanked by short direct repeats of
cellular origin generated during the integration step.

Several enzymatic activities are likely to be required to make the
appropriate scissions and joinings of viral and host DNA during the inte-
grative process. Larry Donehower has been testing the role of a DNA
endonuclease activity present in the products of the viral pol gene. He
has used techniques for in vitro mutagenesis to produce murine leukemia
virus (MLV) pol mutants that retain reverse transcriptase activity but have
lesions in the endonuclease domain. These mutants appear to affect the
integrative mechanism since mutant virus particles can enter cells and
make full-sized unintegrated DNA, both linear and circular forms, but no
virus is produced by the infected cells.

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B. Proviral Signals for Gene Expression

 

Proviruses are templates for synthesis of full~length viral RNA by
host RNA polymerase II. Sequencing of viral LTRs--~in our laboratory by
Ron Swanstrom and John Majors, and elsewhere-~-has revealed customary
signals for initiation and polyadenylation of transcripts. We have also
determined the sequences that are joined post-—transcriptionally to generate
subgenomic, spliced messenger RNAs for env and certain oncogenes. Perry
Hackett, Ron Swanstrom, and Richard Parker have used conventional $-1
mapping procedures to determine splice sites for Rous sarcoma virus (RSV).
Two particularly interesting features emerged: (i) the leader sequence at
the 5' end of subgenomic mRNAs contains a functional translational start
(from the gag gene) that is not used for synthesis of the product of the
viral oncogene, src; and (ii) the splice acceptor site for src mRNA is
derived from the cellular progenitor, c-src, indicating that transduction
of the cellular gene involved recombination within an intron of c- “STC.
John Majors has determined the splice sites for the mouse mammary tumor
virus (MMTV) by sequencing a fortuitously encountered provirus copied
from env mRNA. As in the RSV genome, the splice donor and acceptor sites
conform to deduced consensus sequences for cellular genes; in addition,
no translational start sites are found 5' to the splice junction. One
proposed splicing event, that required to produce an mRNA for pol, remains
uncharacterized because it occurs infrequently and removes few sequences;
Mike Scott has devised a sensitive method of cloning cDNA transcribed from
pol mRNA in hopes of defining the sites involved.

We have been interested in a number of regulatory mechanisms that
appear to depend upon sequences in retroviral LTRs and govern the tran-
scription of viral or linked cellular genes:

(i) An enhancer function, capable of augmenting the transcription of an
adjacent cellular oncogene in a manner independent of orientation and
position, was assigned to the DNA of avian leukosis virus (ALV) in the
light of Greg Payne's study of ALV-induced B cell lymphomas (see below,
B.(2)(a)). Paul Luciw has mapped and characterized this function more
systematically, using an assay in which plasmids containing a herpes
simplex virus thymidine kinase gene (HSV tk) are microinjected into
thymidine kinase (TK ) mouse cells (performed in collaboration with Mario
Capecchi). A region of viral DNA that includes about 100 bp from the 5!
end of the LTR, in any of the four possible arrangements with HSV tk, is
sufficient to increase the efficiency of TK transformation about 20-40
fold; the mechanism augments the likelihood of achieving adequate levels
of expression of HSV tk rather than the chances of stabilizing the micro-
injected plasmid by integration.

(ii) Synthesis of viral RNA from the MMTV LTR is known to be regulated

by glucocorticoid hormones. John Majors has constructed deletion mutants
of a sequenced, steroid responsive MMTV LTR linked to HSV tk or RSV DNA and
has defined a region 120 to 170 bp on the 5' side of the initiation site
that is required for the response. Regulation does not depend upon a

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strict distance between the componentsof a responsive domain, and respon-—
siveness can be conferred upon a heterologous (RSV) promoter. Roel Nusse's
studies of MMTV-induced carcinomas (see below, B.(2)(b)) indicate that the
MMTV provirus also has an enhancer function that acts upon a cellular gene
called int-1 in mammary tumors; we do not yet know whether this type of
enhancement is hormone-dependent.

(iii) The function of LTRs seems to be dependent upon context since
identical units function as promoters at the 5' ends of proviruses and

as polyadenylation sites at the 3' ends. We have been examining this
problem with materials derived from MLV insertion mutants of an RSV
provirus, in which the functions of MLV LTRs appear to suppressed by
surrounding RSV LTRs (Cell 25:23, 1981). Suzanne Ortiz has cloned one of
the inactive MLV LTRs and shown that it can function as a promoter when
freed of adjacent RSV LTRs and reintroduced into cells.

(iv) Expression of RSV proviruses in mammalian cells appears to be
governed by a trans active, negative regulator that extinguishes tran-
scription in a significant proportion of RSV-infected cells. We have
identified an RSV-transformed rat cell in which the regulatory mechanism
does not function, and we are attempting to define components of the regu-
lator. For example, virus recovered from this cell line is subject to
regulation when introduced into new cells, but superinfection of a non-
transformed src mutant of the original line does not establisha regulated
provirus. This suggests that the cell is a regulatory mutant.

C. Retroviruses as Genetic Vectors

 

Retroviruses have demonstrated their ability to transduce cellular
genes and ferry them as part of viral genomes into new cells, where they
are efficiently expressed. We and many others are exploiting this property
of retroviruses to study genes in hand and isolate new ones. Mike Scott
has engineered a series of MLV vectors suitablefor expressing a variety of
cloned genes (or cDNA copies of mRNAs) in the form of gag fusion proteins
or as independent proteins.

_D. Transposable Elements as Analogues of Proviruses

Kevin Mossie has been assessing the possibility that transposable
elements constructed like proviruses in yeast (e.g., Ty-1) or Drosophila
(e.g-, copia) might transpose via RNA intermediates. As a first step, he
has sought unintegrated DNA intermediates that resemble unintegrated forms
of retroviral DNA. Though this search has been unrewarding in yeast, he
has found that many copia~like elements are present as closed circular
molcules both in cultured Drosophila cells and in embryos. The number of
unintegrated molecules varies greatly among the several elements and does
not correlate with the number of integrated copies or the abundance of
transcriptional products.

Il. RETROVIRUSES AS ONCOGENIC AGENTS

Retroviruses competent to induce tumors are conveniently grouped in

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two categories: those highly oncogenic agents that carry oncogenes
transduced from normal cells and those less efficient agents that lack
their own oncogenes. Among the first group are viruses employing about
twenty distinctive oncogenes (v~onc's); our studies have been confined
almost exclusively to the most intensively examined member, v-src, the
oncogene of Rous sarcoma virus (RSV). v-sre encodes a phosphoprotein of
60,000 daltons (ppeo” “SEC) that displays p protein kinase activity in
vitro and induces phosphorylation of tyrosine residues in several p puta~
tive target proteins in vivo. In the second group are a large number of
viruses producing of wide spectrum of diseases; we have focused principally
upon the avian leukosis virus (ALV) and myeloblastosis-associated virus
(MAV), which induce B cell lymphomas and nephroblastomas, and the mouse
mammary tumor virus (MMTV), which induces mammary carcinomas. Viruses
of this second type appear to act as insertional mutagens, enhancing the
expression of adjacent cellular oncogenes as an initial step in tumori-
geneis. We are also interested in other kinds of mutations (e.g., ampli-
fications and translocations) that affect cellular oncogenes in various
tumors, including those in man. These studies have been performed
principally in collaboration with Mike Bishop and are described in his
report.

A. The Function of the sre Gene of RSV.

 

(1) Analysis of mutants of sre.

We have recently isolated a large group of non-conditional src
mutants arising spontaneously in an RSV provirus integrated in the
genome of an infected rat cell. These mutants make full sized products
without protein kinase activity (presumably due to missense mutations) or
truncated proteins (presumably due to nonsense or frameshift mutations).
Graeme Mardon has cloned and sequenced two of the mutant alleles that
encode truncated proteins andhas identified frameshift mutations. In one
case, the position of the lesion allowed detection of an unexpected initi-
ation site for translation in a second sre reading frame, implying that
the wild-type gene encodes a 7,000 dalton protein as well as pp60 ——.
Both frameshift mutants have undergone secondary changes that at least
partially restore the wild type phenotype. In one instance, the genetic
revertant exhibits a duplicated domain of src and encodes an atypically
large protein. Mary Anne Schofield has shown that this protein has about
50% of the normal src kinase activity and induces a partial phenotype:
the cells are transformed by some criteria but do not form colonies in
agar or tumors in animals. A number of the mutant proteins display
different characteristics when expressed in rat or chicken cells; host
dependent mutants of this type are jikely to help identify host functions
required for the action of pp6o™ “St ,

(2) Effect of altered doses of v-sre and c-sre. To examine the
level of pp60Y"STC required to elicit components of the transformed
phenotype, Eddy Jacobovits and John Majors have placed v-sre under the
control of the MMTV LTR. The phenotype of rat cells containing such
hybrid genes displays a dramatic dependence upon glucocorticoid hormones:
a five-fold induction of the expression of sre permits cells to form colonies

 

189
in soft agar, an attribute that generally correlates with tumorigenicity.
Could these differences in dose explain the non-oncogenic behaviour of
normal cells, in which c-sre is expressed at very low levels? Richard
Parker has expressed the cloned chicken c- src gene in rat cells under
control of an SV-40 promoter at levels higher than those required to
achieve complete transformation by v-src. Under these conditions, the
cells manifest no evidence of transformation, indicating that the c-sre
gene product is qualitatively different from pp6o” “SEE,

B. Oncogenesis by retroviruses without viral oncogenes.

(1) ALV induced B cell lymphomas. During his graduate training,
Greg Payne showed that ALV proviruses could initiate tumorigenesis by
enhancing RNA synthesis from the cellular oncogene, c-myc, in any of
three arrangements: with the provirus on the 5' side of the coding
region for c-myc in the same transcriptional orientation, on the 5!
side in the opposite orientation, and on the 3' side in the same orienta
tion. He and Dave Westaway have cloned mutant alleles displaying each of
these arrangements, subjected them to further analysis, and found additional
mutations in the regions of the insertion mutations. In one case, homologous
recombination has occurred between the ALV LTRs, leaving a single LTR posi-
tioned to act as a promoter for c-myc. In a second case, a provirus on the
5' side of the c-myc coding domain in the opposite orientation has suffered
an internal deletion that prevents viral gene expression; moreover, at
least three base substitutions appear to have occurred in one of the c-myc
exons. This suggests that somatic mutations may render oncogenes more
potent at activated loci.

 

We still have an incomplete picture of the structure of the chicken
c-myc gene and its products. Carol Nottenberg has constructed a cDNA
library from a tumor with a proviral insertion on the 3' side of the gene;
analysis of isolated c-myc-specific clones should indicate the boundaries
of c-myc exons with precision.

(2) MMTV-induced mammary carcinomas. Roel Nusse has used the technique
known as "transposon tagging" to identify a novel cellular gene (called
int-i that serves as a target for insertion mutation during tumor induction
by | MMTV. A provirus cloned from a tumor with a single insertion of viral DNA was
shown to be positioned in a domain of about 20 kb that harbored proviruses
in about 75% of tumors in C3H mice. The proviruses are present on both
sides of a transcriptional unit; they are generally pointed away from the
transcribed region and hence act as enhancers rather than promoters of
int-1. Roel and Dave Cox have located int-1 on chromosome 15 of the mouse,
Teddy Fung has shown it is highly conserved and has cloned its homologue
from a Drosophila DNA library. Int-1 is unrelated to available retroviral
oncogenes, and its function is unknown; Teddy Fung has recently isolated
many cDNA clones of int-1 made from tumor RNA, in hopes of generating
reagents for production of antisera.

 

(3) MAV-~induced nephroblastoma. On the assumption that MAV induces
renal tumors by activating cellular genes, Dave Westaway has sought the
target for insertion mutation. However, none of the cellular homologues
of retroviral oncogenes appear to be rearranged by proviruses in these

 

190
tumors, and the cellular sequences linked to a solitary MAV provirus in
one tumor are not interrupted in 15 other tumors. The search continues.

Lil. HEPATITIS B VIRUSES AS ANALOGUES OF RETROVIRUSES

The hepatitis B viruses of man and other animals--~woodchucks,
ground squirrels, and ducks--~have some striking resemblances to retro-
viruses. Recent reports from Summers and Mason at the Institute for
Cancer Research indicate that these viruses replicate their DNA genomes
through RNA intermediates, using a viral enzyme to synthesize viral DNA
from an RNA template in the final phase of the life cycle. Secondly, the
hepatitis B viruses frequently establish a chronic infection and their
genomes are sometimes integrated into the host genome, though not apparently
with the specificity manifest by retroviruses. In addition, the human and
woodchuck viruses seem to have a role in the generation of primary hepato-
cellular carcinoma (hepatoma), a tumor arising after long latency and often
carrying integrated viral DNA.

A. Replication of a Hepatitis B Type Virus of Ground Squirrels (GSHV).

 

Since the hepatitis B viruses do not replicate in cultured cells and
have a narrow host range (infecting specific cell types in selected species),
it is usually necessary to study their replication in infected livers of
their natural hosts. To this end, Don Ganem, later joined by Barbara
Weiser, established a colony of Beechey ground squirrels at the University
of San Francisco, with the help of Dr. James Brown and several pre-medical
students. Our colony, approximately 160 animals strong, was trapped in
Palo Alto and consists mainly of uninfected animals that are susceptible
to virus strains obtained from other animals in the same field. Don and
Barbara have shown that they can transmit these virus strains serially in
our animals; about two-thirds of the animals produce virus about six weeks
after infection and about 15% remain infected chronically (6 months to 2
years or more). However, we find very little or no evidence of inflammatory
change and have observed no hepatomas; hence GSHV appears to be non-pathogenic.

Don Ganem and Linda Greenbaum (a visiting medical student from Columbia
University) obtained several molecular clones of the genomes of two strains
of GSHV and generated physical maps with restriction enzymes. Christoph
Seeger has recently shown that one of these cloned genomes is infectious
when introduced directly into the liver in the form of dimers or re-
circularized monomers. Virus can be recovered from the serum approximately
3 months after intra~hepatic injection of DNA, opening the first prospects
for a genetic analysis of this virus. Christoph has determined the complete
nucleotide sequence of the infectious genome: the arrangement of coding
domains is very similar to that observed in the genomes of the wood-
chuck and human hepatitis B viruses, with extensive use of overlapping
reading frames. In addition, the GSHV genome is strikingly similar to
that of the (pathogenic) woodchuck virus, with sufficient conservation
of restriction sites to permit the construction of recombinant genomes
in vitro. These recombinants are being tested in animals to seek the
determinants of host range and pathogenicity in the two genomes.

Sequential liver biopsies from animals infected in captivity provide
a rich source of GSHV-specific nucleic acids. Barbara Weiser has identified

191
closed circular viral DNA and a heterogeneous collection of partially
duplex molecules in which one strand (that complementary to viral RNA)

is about ten fold more abundant than the other. This strand, like one

of the strands in virion DNA, is tightly bound to an unidentified protein
that is likely to serve as a primer in DNA synthesis. Our results are
consistent with the model proposed by Summers and Mason, and we have
proposed that the circular DNA is transcribed into RNA that serves as a
template for reverse transcription. GSHV RNA in infected liver is complex;
Greg Enders and Don Ganem have found at least two species of polyadenylated
RNA, genomic and subgenomic in length. Further definition is in progress.

B. The Oncogenic Role of Human Hepatitis B Virus (HBV).

 

We are attempting to decipher the role of HBV in human hepatomas
using a series of tumors sent to us by colleagues at the Queen Mary
Hospital in Hong Kong. Tumors from HBV-~infected patients generally
contain integrated HBV DNA; in one case Teddy Fung found a single in-
sertion of HBV DNA. This viral insert was cloned in lambda phage and
flanking cellular DNA was obtained for use as probes for insertions
within the same locus in other tumors. To date we have obtained no
evidence for a common target that would suggest insertion mutations of
cellular oncogenes by HBV DNA. Similarly, DNA from our tumors Fails to
transform cultured mouse 3T3 cells, in experiments performed in collabo-
ration with Robert Weinberg's laboratory at MIT. Since we lack evidence
for viral oncogenes, insertion mutations, or transforming genes in HBV-
induced tumors, the role of the virus remains uncertain.

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1982-1983 PUBLICATIONS

 

Books

"The Molecular Biology of Tumor Viruses, Part III, RNA Tumor
Viruses." J. Coffin, N. Teich, H.E. Varmus and R. Weiss.
Cold Spring Harbor Press, New York (1982).

"Readings in Tumor Virology." H. Varmus and A.J. Levine, eds.
Cold Spring Harbor Laboratory, 1983.

Reviews

Varmus, H.E. and Swanstrom, R. Replication of retroviruses. In
"Molecular Biology of Tumor Viruses, Part III RNA Tumor
Viruses" (Coffin, Teich, Varmus and Weiss, eds.), Cold Spring
Harbor Press, New York, pp. 369-512 (1982).

Bishop, J.M. and Varmus, H.E. Functions and origins of retroviral
transforming genes. In "Molecular Biology of Tumor Viruses,
Part III RNA Tumor Viruses" (Coffin, Teich, Varmus and Weiss,
eds.), Cold Spring Harbor Press, New York, pp. 999-1108 (1982).

Varmus, H.E. (1982). Form and function of retroviral proviruses.
Science 216, 209-217.

Varmus, H.E. (1983). Recent evidence for oncogenesis by insertion
mutagenesis and gene activation. Cancer Surveys 2, 309-319.

Varmus, H.E. Retroviruses. In "Mobile Genetic Elements" (Shapiro,
ed.), Academic Press, New York, pp. 411-503 (1983).

Varmus, H.E., Payne, G.S., Nusse, R., Luciw, P., Westaway, D. and
Bishop, J.M. Insertional mechanisms in oncogenesis by retro-
viruses. In "Perspectives on Genes and the Molecular Biology
of Cancer" (Robberson, Saunders, eds.), Raven Press, New York,
pp. 237-246 (1983).

Varmus, H.E. (1982). A growing role for reverse transcription.
Nature 299, 204-205.

Varmus, H.E. (1983). Reverse transcription in plants? Nature,
304, 116-117.

Research Articles

Hackett, P.B., Swanstrom, R., Varmus, H.E. and Bishop, J.M. (1982).
The leader sequence of the subgenomic messenger RNAs of Rous
sarcoma virus is approximately 390 nucleotides. J. Virol.

41, 527-534.

Swanstrom, R., Varmus, H.E. and Bishop, J.M. (1982). Nucleotide

sequence of the 5' noncoding region and part of the gag gene
of Rous sarcoma virus. J. Virol. 41, 535-541.

193
Payne, G.S., Bishop, J.M. and Varmus, H.E. (1982). Multiple
arrangements of viral DNA and an activated host oncogene
(c-myc) in bursal lymphomas. Nature 295, 209-217.

Swanstrom, R., Bishop, J.M. and Varmus, H.E. (1982). Structure
of a replication intermediate in the synthesis of Rous sarcoma
virus DNA in vivo. J. Virol. 42, 337-341.

Ganem, D., Weiser, B., Barchuk, A., Brown, R.J. and Varmus, H.E.
(1982). Biological characterization of acute infection with
ground squirrel hepatitis virus. J. Virol. 44, 366-373.

Ganem, D., Greenbaum, L. and Varmus, H.E. (1982). Virion DNA of
ground squirrel hepatitis virus: structural analysis and
molecular cloning. J. Virol. 44, 374-383.

Nusse, R. and Varmus, H.E. (1982). Many tumors induced by the
mouse mammary tumor virus contain a provirus integrated in
the same region of the host genome. Cell 31, 99-109.

Mardon, G. and Varmus, H.E. (1983). Analysis of a frameshift
mutant in a Rous sarcoma provirus suggests src contains two
functional sites for the initiation of protein synthesis
from a single mRNA. Cell 32, 871-879.

Luciw, P., Bishop, J.M., Varmus, H.E. and Capecchi, M. (1983).
Location and function of retroviral and SV40 sequences that
enhance biochemical transformation after microinjection of
DNA. Celli 33, 705-716.

Alitalo, K., Schwab, M., Lin, C.C., Varmus, H.E. and Bishop, J.M.
(1982). Homogeneously staining chromosomal regions contain
amplified copies of an abundantly cellular oncogene (c-myc)
in malignant neuroendocrine cells from a human colon carcinoma.
Proc. Natl. Acad. Sci. USA 80, 1707-1711.

Swanstrom, R., Parker, R.C., Varmus, H.E. and Bishop, J.M. (1983).
Transduction of a cellular oncogene: the genesis of Rous sar-
coma virus. Proc. Natl. Acad. Sci. USA 80, 2519-2523.

Schwab, M., Alitalo, K., Varmus, H.E. and Bishop, J.M. (1983).
A cellular oncogene (c-Ki-ras) is amplified, overexpressed,
and located within karyotypic abnormalities in mouse adreno-
cortical tumor cells. Nature 303, 497-501.

Weiser, B., Ganem, D., Seeger, C. and Varmus, H.E. (1983).
Closed circular viral DNA and asymmetric heterogeneous forms
in livers from animals infected with ground squirrel hepatitis
virus. J. Virol., in press.

Majors, J.E. and Varmus, H.E. (1983). Nucleotide sequencing of

an apparent proviral copy of env mRNA defines determinants of
expression of the MMTV env gene. J. Virol., in press.

194
Majors, J.E. and Varmus, H.E. (1983). A small region of the mouse
mammary tumor virus long terminal repeat confers glucocorticoid
hormone regulation on a linked heterologous gene. Proc. Natl.
Acad. Sci. USA, in press.

MAJOR RESEARCH SUPPORT

 

Source:
Title:

Total period
of award:

Source:
Title:

Total period
of award:

Source:
Title:

Total period

American Cancer Society (MV481)
Biochemical aspects of Rous sarcoma virus.

January 1, 1983 to December 31, 1983.

National Institutes of Health (CA 19287-07)
Molecular biology of mouse mammary tumor virus.

July 1, 1976 to June 30, 1986.

National Institutes of Health
The molecular biology of hepatitis B-type
viruses.

of award: September 1, 1982 to August 31, 1985.
_ PERSONNEL

Delicia Caballero Lab Helper

Lawrence Donehower Postdoctoral Fellow

Gregory Enders

Yuen Kai Fung

Graduate Student
Postdoctoral Fellow

Edward Jakobovits Postdoctoral Fellow

Graeme Mardon

Janine Marinos

Kevin Mossie

Staff Research Associate
Administrative Assistant
Graduate Student

Carol Nottenberg Postdoctoral Fellow

Suzanne Ortiz
David Persing

Staff Research Associate
Graduate Student

Mary Anne Schofield Graduate Student

Michael Scott
Raymond Scott

Postdoctoral Fellow
Lab Helper

Christoph Seeger Postdoctoral Fellow

Barbara Weiser
David Westaway

Postdoctoral Fellow
Postdoctoral Fellow

PERSONNEL WHO LEFT THE LABORATORY 1982-1983

 

Donald Ganem

Paul Luciw

Assistant Professor of Medicine and
Microbiology and Immunology, UCSF
Staff Scientist, Chiron Corporation
Emeryville, California

195
John Majors
Richard Parker

Gregory Payne
Roel Nusse

Assistant Professor of Biochemistry,
Washington University

Assistant Professor of Microbiology,
Columbia University

Postdoctoral Fellow, UCB

Staff Member, Antoni van Leeuwenhoekhuis,
Department of Virology, Amsterdam

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