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education

A brief history of
AIDS
Robert C Gallo, one of the co-discoverers
of HIV, gives a personal and historical
insight into 25 years of the disease

n 1981 newspaper stories started

appearing about a collection of
cases of unusual fungal and
parasitic infections, especially
Pneumocystis carinii, in the east
coast of the United States. Articles
followed about cases of the rare
neoplasia known as Kaposis sarcoma
from the west coast in homosexual
men. Strange though they were, these
cases were not important or exciting
enough to change your career. I was
working on leukaemia at the National
Cancer Institute in Bethesda, and the
reports came at a tranquil and
pleasant moment in my life.1-3
We had learnt how to grow T cells
for the first time only five years
earlier.4 5 This was based on our
discovery of a growth factor activity
for T cells now known as interleukin
2. In turn the ability to culture and
replicate T cells coupled with sensitive
specific assays for reverse transcriptase67 led to our discovery of human T
cell leukaemia/lymphoma virus type I
(HTLV-1), one of the first identified
viruses that causes cancer in humans.8-10.
Reverse transcriptase is a DNA
polymerase,
like
the
DNA
polymerases in our cells. All catalyse
the synthesis of DNA from a DNA
template, but reverse transcriptase is
special because it also transcribes
RNA into DNAa feat previously
unknown in biology.11 12 Because
reverse transcriptase is found in all
animal retroviruses and because tests

450

for it could be made sensitive, fast, and

specific, we adapted it as a surrogate
marker in our search for a human
retrovirus.
HTLV-1 causes a T cell leukaemia,
usually of CD4 T cells, often in young
adults.13 This was the first known
leukaemia virus in humans, and the
quest for it was long, controversial,
and more difficult than finding HIV.
By 1981 we knew that HTLV-1 was
transmitted by blood, by sex, and from
mother to infant, especially by breast
feeding, and we knew it could impair
immunity. In the same period of 1981
we found a second human retrovirus
(HTLV-2).9 10 14 We were excited by this
work and began to focus on how the
virus caused leukaemia when the
AIDS problem gained more significance because of increasing numbers
and the mysteries surrounding it.
Finally, after listening to a lecture at
the US National Institutes of Health
by James Curran of the Centers for
Disease Control and Prevention, the
pioneering epidemiologist of AIDS, I
was stimulated to think seriously
about this problem. Led by Curran,
the Centers for Disease Control and
Prevention made the first reports on
the original AIDS cases in their
publication.
Here was a new disease, and
Curran told us if it was because of an
infectious agent then its transmission
would likely be by blood (haemophiliacs and intravenous drug misusers

were affected), sex, and mother to

infant. Clinicians told us that it
seemed that the main immune
impairment involved CD4 T cells. All
these things fitted with what we knew
about human retroviruses. Moreover,
AIDS seemed to be prevalent in Haiti
and tropical Africa. These were places
we knew HTLVs to be prevalent.
Consequently, in 1982 along with
Max Essex in Boston, I postulated that
the cause of AIDS would likely be
another human retrovirus, one I
logically assumed would belong to the
HTLV family. This idea was the only
one that bore fruit. The cause of AIDS
was indeed a new retrovirus, but one
distinct from the HTLV family.

One milestone after another

We began our research in May 1982
by exploring T cells from patients with
AIDS for HTLV related retroviruses
using molecular probes and testing
serums for antibodies. We also began
culturing T cells from the blood of
some patients with AIDS in an
attempt to detect and then isolate a
putative new retrovirus. In early 1983
we reported and described a few
positive results, but because of looking
for HTLV relatedness, these samples
were always mixed with and
dominated by HTLV. In other words,
these were patients infected with both
HTLV and HIV.15 At the same time,
Luc Montagnier and his colleagues in
Paris reported detection of an
unambiguously new retrovirus in a
patient with lymph gland enlargement that later would be proved to be
the AIDS virus.16
Our original problem was the
mixture of retroviruses, whereas
Montagniers problem was the
inability to sustain his strain of HIV in
continuous culture. Neither group
could at that time claim that its work
showed that the viruses caused AIDS.
That would happen exactly a year
later, in 1984, when my colleagues
and I were able to find HIV in 48
patients with AIDS or in people in so
called AIDS risk groups.17 We were
also able to continuously propagate
the virus in cell line culture,18 a critical
advance that led to early characterisation of HIV proteins19 and the
development of the serum antibody
based HIV blood test.1921 The blood
test enabled us to screen hundreds
and ultimately thousands of serums.
Along with the many isolates of the
virus,17 the evidence that it targeted
CD4 T cells,16 18 and the fact that like
AIDS the virus was also new, as well
as some other considerations22 led us
to conclude that HIV was the cause of
AIDS.
Of course, the blood test also had
immense practical effects for the field.
The blood supply used for medical
purposesfor transfusionscould now
be protected. The epidemic could be
followed because no longer
would we have to wait to see
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Wafting through chaos

Finding the cause of AIDS presented
unusual challenges. Firstly, because the
signs of disease were not seen until
after a decade after infection it meant
that the clues were scant. Secondly, the
disease was usually associated with
multiple opportunistic infections by
the time it appeared. Which infection
was the cause? In this respect the
blood test was indispensable because it
was safe to do, sensitive, specific, rapid,
and inexpensive. This made it useful
on a global scale.
Once the cause was established and
all the necessary reagents made
availablefor example, virus cultures,
HIV molecular probes, specific
antibodies, and so onthe field
exploded. Those early years of 1982-5
may represent the fastest pace ever
achieved in medical science from the
time of the birth of a new disease to
advances in its understanding,
diagnosis, prevention, and treatment.
Additional advances in this earliest
period included the finding of HIV
related retroviruses in monkeys
(simian immunodeficiency virus, SIV),
the use of SIV in some monkeys to

induce AIDS,2526 and use of this model

for experimental studies of pathogenesis and vaccine research.
At the same time that these tunes
were filled with excitement as we
watched the mysteries of the new
epidemic all one by one, they were
also filled with worries, stress, puzzlement, and frank confusion. Much of
this, of course, was caused by a new
mystery: how could we best take
advantage of our knowledge about
HIV to help end the epidemic? For
example, how much should we virologists turn ourselves into vaccinologists? This question weighed on me
especially, because I soon learnt that
no one person or group was really
responsible for developing a vaccine.
Worse, the vaccinologists I spoke with
were much too ill informed about the
special characteristics of retroviruses.
The medical-scientific issues were,
however, only a fraction of our
concerns. Soon we would be dealing
with patients issues related to the
blood test for HIV; facing lawyers and
public relations firms; and enduring
the wrath of activists, many of whom
were patients. To my knowledge this
was another historical first in
medicine. The anger shown by
activists towards scientists was partly
to draw attention to the activists
cause. Their real anger was because of
the impression that society as a whole,
and government in particular, were
not doing enough. Some of their
anger towards us, however, was real.
They saw the blood test as a tattoo
that marked them at a time when
prejudices were running high.
Although they soon realised the
necessity of the blood test and the
great advances made possible by it,
they were initially in a hopeless state
with no treatment except the less than
optimal options for secondary
opportunistic infections. In the end,
the activists became our greatest
supporters and sometimes gave us

education

the signs of AIDS (usually needing

some 5 to 15 years); now we could
follow infection almost from the
onset. Education programmes could
be accelerated and individual patients
advised. The systems developed for
continuous cell line production of
HIV also yielded practical beneficial
results. They were used to test drugs
against HIV, beginning another
medical historic and dramatic aspect
to the story, namely the first successful
antiviral treatment. This began with
zidovudine (azidothymidine, AZT),23
and culminated in the triple drug
therapy24 now called HAART (highly
active antiretroviral treatment) that
was launched in the mid-1990s and
developed by many groups.

new insights into the disease. Looking

back, though, I realise how we
physician-scientists are unprepared to
deal with many issues, such as patients
and lawyers, public relations and the
media, and activists.
In those early days, we could anticipate many of the developments that
occurred in the next 20 years. From
our serological studies we knew from
the start that AIDS would soon be
global, but no one could have possibly
anticipated
the
great
African
catastrophe. From its nature as a
retrovirus we also knew that HIV
infection would be life long for the
patient and would not quickly go
away, like most epidemics. HIV was
here to stay unless abolished by
scientific success with a preventive
vaccine. We suspected that a
successful vaccine against HIV would
be exceptionally difficult to make, not
only because of the viruss variability
but even more importantly because of
the capacity of a retrovirus to
integrate its genetic information into
its target cell within a few days (or less)
from the time of infection. With this
characteristic comes real trouble
because it implies we may have to
block infection completely and from
the onset, and this has never been
achieved with any vaccine before.
Treatment is another matter. I must
confess I was pessimistic about the
prospects of effectively treating HIV.
Because viruses are so much a part of
us, they provide few specific targets.
Also retroviral infections are life long,
thereby rendering any virological cure
almost impossible. Consequently,
treatment would need to be life long
and would be accompanied by the
toxicity and viral drug resistance
problems that are likely to occur with
decades
of
treatment.
Some
therapeutic successes were evident by
the mid to late 1980s, however, and
important
advances
in
treatment would happen soon.

Adult HIV prevalence %

1550
515
15
0.51.0
0.10.5
0.00.1
No data

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education
A fascinating
assassin

452

Putting science ahead

Almost 23 years have passed since we
found the cause of AIDS. Almost all
the important advances in HIV/AIDS
research were made in the early
period of 1982-5, which in turn led to
every practical application that affects
infected people. Surely subsequent
work has been important and will be
essential to the final solution
removing HIV from the human
population.
Where are we today, and what are
the major problems? HIV has killed
about 30 million people and about
40 million are infected. My colleague,
the epidemiologist William Blattner,
likes to point out that the Indian
Ocean tsunami of 2004 killed an
estimated 230 000 people. HIV is
akin to a tsunami killing more than
250 000 people every month. But can
we expect things to improve? I
believe this is impossible to predict
because the epidemic is still in a
dynamic state and because it is
equally difficult to predict human
behaviour or sustained governmental
support. For example, if another
attention grabbing calamity affects
the globe, HIV may not be seen as so
critical a problem.
And increasing number of HIV
variants, including recombinant
forms, may not behave like the earliest
HIV strains in response to treatment
and resistance to drugs. And this is

not an infectious agent that is going to

go away on its own. Retroviruses
generally establish permanent or at
least long lasting infections within a
species. Conversely, I believe it is
impossible for HIV to evolve into a
casually transmissible virus. This
would change its cellular tropism to
such an extent that it would be
unlikely it could still target critical cells
of our immune system. Indeed, I
know of no case of a retrovirus in any
species that is casually transmitted.
The future depends in part on
expanding
blood
testing
and
promoting education throughout the
world. It also depends on distribution of
the various anti-HIV drugs to people in
need, and all depend upon sustained
financing and commitment by many
parts of society. The HIV/AIDS
problem takes more than medical
scientists and clinicians. It necessarily
involves other social and healthcare
workers and support groups. Nevertheless, I fear that their growing involvement could overshadow the paramount
role that must be played by science. We
have already seen this phenomenon
occur at some of the large international
AIDS meetings. This may also be
aggravated by what I see as a growing
gap between scientists and people not
so engaged because of the increasing
technical complexity of medical
research.
We must never forget the essential

role still to be played by medical

science. We have effective treatment
only because of the basic research
into HIV. Because life long treatment
is needed, drug resistance and
toxicity occur, and this demands new
forms of treatment, which in turn are
forthcoming only from more
research. So far science has managed
to keep up with the virus, although a
virological cure has not been
attained, nor is one likely. The
ultimate answer, of course, is a
successful preventive vaccine. The
difficulties in developing a vaccine
for any retrovirus are formidable,
and even more so for HIV because
of its variability.27 Causes for hope
spring from the recent advances in
our understanding of some of the
details of HIV entry into the cell28-34
and the structure of the HIV
envelope.35 36 My current thoughts
lean towards optimism. If we are
correct, perhaps we can envisage that
this will be the last time that a 25 year
reflection is needed.
Robert C Gallo professor, Departments of
Microbiology and Immunology and Medicine,
University of Maryland Baltimore, Baltimore,
MD, USA
gallo@umbi.umd.edu

Competing interests: None declared.

References 1-36 are on studentbmj.com.
STUDENTBMJ | VOLUME 14 | DECEMBER 2006