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Canberra
I was invited to succeed Frank Fenner as Head of the Department
of Microbiology at the John Curtin School and took up the position in
late 1968. Though much was known about the humoral response to viral
infections, knowledge about cell-mediated immune responses was almost
non-existent. I thought that if research projects combining both virological
and immunological approaches were strongly encouraged, supported by
basic research in Virology and Immunology, surely some exciting findings
would be made.
For example, Parish was the first to show the inverse relationship
between antibody and cell-mediated immune responses which in turn led
to the description of two classes of helper T cells by others. Bruce
Stillman's studies on adenovirus started him on the road to becoming
Director of the renowned Cold Spring Harbor Laboratories in New York
State. Robert Blanden was studying the immune response to ectromelia,
a pox virus pathogenic for mice. In the next few years, he brought back
from overseas meetings the technology for assaying the newly discovered
cell population called cytotoxic T cells (CTLs). He became the first
to show that this particular T cell response was responsible for clearing
an ectromelia infection but information on how these cells recognised
virus-infected cells was completely unknown though there were early
indications that major histocompatibility (MHC) antigens were involved
in some way. Some inbred mouse strains were imported to facilitate further
studies. Peter Doherty, a fresh Ph.D. graduate, came to the department
as a postdoctoral fellow in 1972, and started work on lymphocytic choriomeningitis
(LCM) virus infections of mice. Rolf Zinkernagel, a Swiss medical graduate,
came out initially on a Swiss Fellowship but later was awarded an ANU
PhD scholarship.
On arrival in Canberra in early 1973, Rolf worked for a while with
Blanden to learn about assaying CTL activity and then I asked Peter
and Rolf to share the same laboratory. In some very elegant experiments,
they found that cytotoxic T cells formed during a LCM viral infection
would only lyse infected target cells if effector and target cells shared
at least some MHC antigen specificities, that is, the T cell lytic activity
was 'MHC restricted'.They suggested that the cytotoxic T cell receptor
recognised at the infected cell surface some virus-induced alteration
of the MHC molecule, possibly caused by complexing with a viral antigen.
They proposed the fundamental concept - that a central function of MHC
antigens was to signal changes in 'self' i.e.,to what they now called
'altered self', to the immune system. Once identified, such a cell would
be lysed.
This finding stimulated much research both in the Department and especially
overseas, and studies investigating the details of MHC restriction of
T cell responses became a leading immunological topic internationally.
Both Rolf and Peter left to work overseas in the mid 1970s. Until my
retirement in 1987, my group studied in detail the activation and roles
of T cells in murine influenza. For example, we showed that infected
cells were recognised by CTLs within 1-2 hours after infection, many
hours before infectious viral progeny was produced. This gave a window
of time for the cytotoxic T cell to find an infected cell and destroy
it before viral progeny were released and could infect other cells.
Subsequently, analysis of crystals of MHC molecules isolated from the
surface of infected cells by groups in the USA showed a viral peptide
occupying a cleft in the MHC molecule so that parts of each were recognised
by the CTL receptor.
The award of the 1996 Nobel Prize in Physiology or Medicine to Rolf
and Peter recognised the importance of their original discovery, as
it was the first description of the molecular mechanism used by vertebrates
for the control and clearance of most intracellular infectious agents,
especially viruses.
Geneva and Stockholm
For 20 years beginning in 1971, I successively became associated with
eight different Programmes of the World Health Organization, most being
concerned with the development and use of vaccines. These experiences
caused my own research to concentrate on defining the roles of different
components of the immune response to viral infections.
As I approached retirement (December, 1987), I was invited to do a
six month consultancy at WHO, to spend my retirement at Johns Hopkins
School of Hygiene and Public Health (JHSHPH), Baltimore, by Dr. Noel
Rose, and finally, to give the plenary lecture on 'The prospects for
HIV Vaccines' at the Fourth International AIDS Congress in Stockholm
in May, 1988. By 1986, HIV RNA had been largely sequenced, and there
was great optimism that a vaccine could quickly be developed. In the
next two years, however, several disturbing findings were made, especially
the very great sequence variation of the envelope antigen in different
HIV isolates. At the Stockholm talk, I listed 7 reasons why it would
be very difficult to develop an HIV vaccine based primarily on strong
infectivity-neutralising antibody formation.
Two of my Canberra departmental colleagues, David Boyle and Ian Ramshaw,
had shown that DNA coding for antigens of other infectious agents and
of cytokines could be inserted into the DNA of a pox virus, such as
vaccinia virus. Vaccination with this 'chimeric' virus could protect
against persistent infection by the agent which was the source of the
inserted DNA. Drawing on this recent research, I suggested that because
the internal antigens of HIV, which are the source of many T cell epitopes,
showed considerably less variation, a vaccine might be developed based
on vaccinia virus containing the genes coding for the internal HIV antigens,
gag and pol, as well as for the cytokine, interferon gamma. In mice,
such a construct generated a strong cytotoxic T cell response; in man,
this might be sufficient to better control, if not clear, an HIV infection.
The 8,000-strong audience was largely stunned by my assessment of the
situation, though none subsequently disputed it. However, major vaccine
manufacturers ignored it, determined to make an antibody-inducing subunit
vaccine based on the HIV envelope antigen. Baltimore, Washington. On
arrival in Baltimore in July, 1988, I was warmly welcomed, made Associate
Director of a new Center for AIDS Research and later became Director.
In Washington, I was asked to participate in meetings and activities
of the Division of AIDS (D.AIDS), of the National Institute of Allergy
and Infectious Disease (NIAID). Though my wife and I decided to return
to Australia in 1991 after three years in the USA, I was invited to
continue the relationship with D.AIDS and to join a new HIV vaccine
working group. The crunch came in 1995 when the Director of the NIAID
refused to support a phase III clinical trial of the then leading HIV
candidate vaccine, based on the envelope antigen. Many reasons were
given but two critical ones were:
- Antibody from volunteers immunised with this candidate vaccine did
not prevent infection by newly isolated HIV field strains; and
- The vaccine did not induce cytotoxic T cell formation in the volunteers.
This was a major turning point in international research aimed at developing
an HIV vaccine. NIAID decided to completely revamp their HIV vaccine
development programme, and my hectic travel schedule to and from the
USA came to an end. My last task for the Working Group was to review
the evidence supporting a role for cytotoxic T cells in controlling
HIV infections. Back to Canberra.
On my return, I was appointed Visiting Fellow in the (now) Division
of Immunology and Cell Biology at the John Curtin School, and appointed
chairman of the Australian HIV Vaccine Working Group in Sydney. Ian
Ramshaw had recently shown that a vaccination schedule involving priming
with plasmids containing DNA coding for selected antigens, followed
by boosting with chimeric fowlpox virus coding for the same antigens
gave a greatly enhanced immune response in mice. Stephen Kent (now University
of Melbourne) and Ramshaw, with colleagues, showed that M. nemistrina
monkeys immunised in this way developed a strong cytotoxic T cell response
and rapidly cleared a subsequent HIV infection. Any antibody induced
was irrelevant. Supporting findings for this approach were later reported
from the USA. It now seemed that Australia could develop an HIV vaccine
initiative based on this vaccination technology. At a meeting of the
HIV Vaccine Working Group, Prof. David Cooper was elected to Head an
Australian HIV Vaccine Consortium. Earlier this year, out of 20 international
applications received, the NIAID awarded four contracts, three to USA
groups and the fourth to the Australian consortium ($AUS27 million over
5 years) to carry out clinical trials of their vaccine formulation.
It is anticipated that a strong immune capability based on cytotoxic
T lymphocyte activity will greatly reduce viral titres so that those
infected by HIV will live longer and be much less infective for others.
If this vaccination technology can be shown to generate strong CTL
responses in humans, it heralds a new approach to control other difficult
infectious diseases, caused by plasmodia (malaria), chlamydia (trachoma
and pelvic inflammatory disease) and even pandemic influenza.
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