Clin.
exp.
Immunol.
(1984)
56,
1-13.
OR
1'0
C
4>
REVIEW
Sciences
The
acquired
immune
deficiency
syndrome
A.
J.
PINCHING
Department
of
Immunology,
St
Mary's
Hospital
Medical
School,
London,
UK
(Acceptedfor
publication
20
December
1983)
INTRODUCTION
The
emergence
of
a
new
and
epidemic
form
of
acquired
cellular
immunodeficiency
over
the
last
5
years
has
had
wide
ranging
implications-clinical,
scientific
and
social.
Few
medical
conditions
can
have
caught
the
imagination
of
both
the
public
and
the
scientific
community
so
rapidly
and
so
extensively
as
the
acquired
immune
deficiency
syndrome
(AIDS).
The
exponential
spread
of
the
disease
is
matched
by
the
increasing
literature
on
the
subject
and
our
swiftly
changing
perception
of
the
disease.
While
much
has
been
learnt
about
how
the
disease
behaves,
major
uncertainties
remain
as
to
aetiology
and
pathogenesis.
For
these
reasons
any
review
of
the
disorder,
even
more
than
usual,
reflects
a
highly
personal
view
of
the
evidence
available
at
the
time
of
writing.
Underlying
the
present
eclectic
account
is
a
set
of
hypotheses
that
to
my
mind
best
fit
the
data,
but
I
shall
indicate
where
major
alternatives
exist.
There
are
those
who
feel
that
the
term
'acquired
immune
deficiency
syndrome'
is
less
than
ideal
because
it
ignores
other
recognized
acquired
immune
deficiencies.
While
this
may
be
so,
the
term
is
not
inappropriate
and
is
clearly
used
to
refer
to
the
epidemic
variety.
Alternative
terms
that
have
been
proposed
suggest
aetiological
or
pathogenetic
mechanisms
of
doubtful
validity
or
imply
that
there
are
distinct
syndromes
affecting
the
different
epidemiological
groups.
Few
medical
terms
can
have
so
rapidly
become
part
of
lay
parlance
and
any
attempt
to
change
the
terminology
now
would
seem
as
doomed
to
failure
as
it
is
unnecessary.
The
definition
of
AIDS
used
by
the
Centers
for
Disease
Control
(CDC)
in
Atlanta,
Georgia,
USA
for
epidemiological
purposes
is
'a
reliably
diagnosed
disease
that
is
at
least
moderately
indicative
of
an
underlying
cellular
immune
deficiency'
in
a
person
with
'no
known
underlying
cause
of
cellular
immune
deficiency,
or
other
cause
of
reduced
resistance
reported
to
be
associated
with
that
disease'.
It
may
be
paraphrased
as
meaning
'previously
normal
people
behaving
as
though
they
had
been
immunosuppressed'.
While
the
formal
definition
necessarily
excludes
many
disorders
that
may
ultimately
be
shown
to
be
related
to
AIDS,
it
is
currently
preferable
to
a
more
inclusive
definition
as
it
avoids
introducing
a
heterogeneity
of
aetiologies
that
would
confound
the
search
for
the
cause
of
AIDS.
Once
the
aetiology
has
been
established
we
may
be
able
to
perceive
a
much
broader
spectrum.
THE
CLINICAL
SYNDROME
Table
1
outlines
the
major
disorders
that
have
been
described
in
patients
with
AIDS.
While
Pneumocystis
carinii
pneumonia
and
Kaposi's
sarcoma
are
among
the
most
distinctive
features
and
remain
the
commonest
manifestations,
it
is
the
overall
pattern
of
secondary
diseases
that
best
delineates
the
underlying
basis
for
the
syndrome.
The
list
of
infections
(Gottlieb
et
al.,
1981,
1983;
Masur
et
al.,
1981;
Siegal
et
al.,
1981;
Follansbee
et
al.,
1982;
Mildvan
et
al.,
1982a;
Greene
et
al.,
1982;
Goldfarb
et
al.,
1982;
Masur
et
al.,
1982;
Miller
et
al.,
1982;
Andreani
et
al.,
1983;
De
Jong
et
al.,
1983;
Wormser
et
al.,
1983;
Davis
et
al.,
1983;
Poon
et
al.,
1983;
Elliott
et
al.,
1983;
Vieira
et
al.,
1983;
Pitchenik
et
al.,
1983;
Malebranche
et
al.,
1983;
Pape
et
al.,
1983)
immediately
presents
a
Correspondence:
Dr
Anthony
J.
Pinching,
Department
of
Immunology,
St
Mary's
Hospital
Medical
School,
Norfolk
Place,
London
W2
lPG,
UK.
Table
1.
Major
disorders
in
AIDS
Opportunistic
infections
Tumours
Pneumocy.stis
carinii
Kaposi's
sarcoma
Cytomegalovirus
(reactivation)
Burkitt
like
lymphoma
Herpes
simplex
(locally
invasive)
Unidifferentiated
non-Hodgkin's
lymphoma
Candida
(locally
invasive/disseminated)
CNS
lymphoma
Mvcobacterium
atrium
intracellulare
Angioblastic
lymphadenopathy
Myvcobacterium
tuberculosis
Lymphoblastic
preleukaermia
Criptococcus
neoformans
Toxoplasma
gondii
Salmonella
spp.
Cryptosporidium
Isopora
belli
Papovavirus
Nocardia
Histoplasma
pattern
familiar
from
immunodeficiency
diseases
and,
almost
without
exception,
implies
cellular
immune
deficiency.
The
pattern
has
been
established
in
congenital
disorders
such
as
severe
combined
immunodeficiency
(SCID)
and
in
iatrogenic
immunocompromise
following
immunosup-
pressive
therapy,
such
as
that
after
organ
transplantation.
Similarly,
Kaposi's
sarcoma
(apart
from
the
classical
form)
(Hymes
et
al.,
1981;
Friedman-Kien
et
al.,
1982;
Drew
et
al.,
1982;
Pitchenik
et
al.,
1983;
Pape
et
al.,
1983;
Gottlieb
et
al.,
1983)
and
other
tumours
in
AIDS
(Ziegler
et
al.,
1982;
Snider
et
al.,
1982;
Volberding,
1984)
are
similar
to
those
seen
in
patients
on
long
term
immunosuppressive
therapy
following
organ
transplantation
or
treatment
for
systemic
lupus
erythematosus
(SLE).
Many
of
these
tumours
have
been
associated
with
certain
viral
agents
(cytomegalovirus
[CMV]
and
Epstein-Barr
[EB]
virus)
and
may
be
regarded
as
examples
of
viral
oncogenesis.
It
may
be
useful
to
consider
such
tumours
a
consequence
of
opportunist
infection
with
oncogenic
viruses.
For
convenience
I
shall
refer
to
them
as
opportunist
tumours.
The
novel
occurrence
of
these
opportunist
infections
and
tumours
in
the
same
epidemiological
groups
(see
below)
leads
to
the
hypothesis
that
AIDS
comprises
a
central
underlying
immunodeficiency
that
may
manifest
itself
by
a
wide
variety
of
secondary
diseases.
These
multiple
final
paths
may
vary
in
pattern
according
to
genetic
factors
(e.g.
ethnic
background
and
HLA
DR5
in
Kaposi's
sarcoma,
Friedman-Kien
et
al.,
1982;
Pollack
et
al.,
1983),
exposure
to
environmental
opportunist
pathogens
(differences
between
geographical
areas)
and
previous
exposure
to
microbial
agents
that
can
remain
latent
in
host
cells
(e.g.
CMV
and
Herpes
simplex
in
homosexuals,
toxoplasma
and
M}
cobacterium
tuberculosis
in
Haitians).
The
primary
cause
of
the
immunodeficiency
need
not
be
one
of
the
causes
of
the
opportunist
infections
or
tumours.
A
detailed
description
of
the
clinical
presentations
of
individual
manifestations
of
AIDS
is
beyond
the
scope
of
this
article
and
readers
are
referred
to
the
review
by
Gottlieb
et
al.
(I1983)
as
well
as
to
individual
reports
(see
previous
references).
A
number
of
points
should
however
be
highlighted
because
they
have
direct
implications
for
the
immunological
appraisal
of
AIDS.
In
general
opportunist
disease
in
AIDS
is
more
severe
than
that
seen
in
iatrogenically
immunosuppressed
patients
although
it
may
not
be
so
broad.
In
AIDS
this
certainly
leads
to
more
widespread
or
more
invasive
disease
with
a
higher
yield
of
organisms
(e.g.
Pneumocystis)
and
minimal
or
no
evidence
of
host
response,
either
systemically
or
in
tissue
(e.g.
granulomata
in
Mycobacterial
infection,
Greene
et
al.,
1982).
The
rate
of
progression
of
tumours
similarly
tends
to
be
greater
than
in
other
comparable
settings.
Some
of
the
organisms
are
of
a
type
rarely
seen
even
in
other
immunosup-
pressed
hosts
(e.g.
Mycobacteriumn
atium
intracellulare),
another
indication
of
the
depth
of
immunosuppression.
Further
evidence
of
this
comes
from
the
lesser
efficacy
of
anti-microbial
therapy
for
given
infections
in
AIDS
as
compared
with
other
immunosuppressed
states
(e.g.
failure
to
respond
to
cotrimoxazole
and/or
pentamidine
in
Pneumocystis
infection).
The
high
mortality
A.
J.
Pinching
2
The
acquired
immune
deficiency
syndrome
3
rate
of
AIDS
(over
80%
2
year
mortality)
reflects
the
irreversible
immunodeficiency
and
the
ultimate
development
of
untreatable
opportunist
infections
or
of
extensive
tumour
dissemination.
It
is
notable
that
for
patients
with
opportunist
infections
(with
or
without
tumours)
the
2
year
mortality
is
over
95%
while
it
is
much
less
for
those
with
opportunist
tumours
(Kaposi's
sarcoma
alone,
t
50%
2
year
mortality).
The
better
prognosis
appears
to
apply
where
evidence
of
immunosuppres-
sion
is
least.
Other
evidence
of
disordered
immune
regulation
is
indicated
by
the
occurrence
of
autoimmune
disorders
notably
idiopathic
thrombocytopenic
purpura
(Morris
et
al.,
1982)
and
haemolytic
anaemia-in
the
same
'at
risk'
groups.
Although
initially
ascribed
to
autoantibodies,
these
may
be
immune
complex-mediated
(Karpatkin,
Walsh
&
Morris,
1984).
The
occurrence
of
a
similar
syndrome
in
infants
(O'Reilly
et
al.,
1982;
Oleske
et
al.,
1983;
Rubinstein
et
al.,
1983),
usually
born
to
mothers
with
or
who
subsequently
developed
AIDS,
poses
a
problem
in
distinguishing
such
cases
from
previously
recognized
forms
of
cellular
immunodeficiency
(SCID,
Nezelof's
syndrome).
The
balance
of
evidence
favours
the
view
that
there
is
a
form
of
AIDS
occurring
in
children.
EPIDEMIOLOGY
Existing
surveillance
methods
for
Kaposi's
sarcoma
and
especially
for
Pneumocystis
carindi
pneumonia
in
the
USA
were
able
to
detect
the
emergence
of
these
two
diseases
in
homosexuals
and
other
new
at
risk
groups.
These
surveillance
records
make
it
certain
that
AIDS
was
indeed
new
to
the
USA
in
1978/79
(Auerbach
et
al.,
1982);
all
previous
cases
were
in
individuals
known
to
be
immunosuppressed
or
at
risk
from
Kaposi's.
Similarly
it
is
now
clear
from
records
in
Haiti
that
the
disease
first
appeared
there
at
about
the
same
time
(Malebranche
et
al.,
1983;
Pape
et
al.,
1983;
Leonidas
&
Hyppolite,
1983).
On
the
other
hand,
cases
related
to
Central
Africa
date
back
to
1976
(Bygbjerg,
1983;
Brunet
et
al.,
1983)
and
possibly
much
further
(see
later).
Within
the
USA,
an
exponential
rise
in
cases
has
ensued
with
New
York
apparently
about
a
year
ahead
of
the
West
Coast.
Over
2,500
cases
were
reported
to
the
end
of
October
1983
for
the
USA,
with
a
6
month
doubling
time.
Although
sporadic
cases
have
been
seen
in
Europe
since
the
late
1970s,
in
most
countries
the
major
rise
in
cases
has
occurred
in
1982
(e.g.
France)
or
1983
(e.g.
UK),
some
3
years
behind
the
American
epidemic.
Figures
for
the
whole
of
Europe
exceed
250
and
current
UK
figures
are
26.
While
AIDS
was
first
recognized
in
homosexual
males,
it
is
now
seen
to
affect
a
number
of
distinct
subpopulations
(CDC,
1983):
homosexuals/bisexuals
(71%),
intravenous
drug
abusers
(I17%),
haemophiliacs
and
others
receiving
large
amounts
of
blood
or
blood
products
(I%),
female
sexual
partners
of
AIDS
patients
and
infants
of
females
with
AIDS.
Haitians
(5%)
and
residents
of
Central
Africa,
both
at
home
and
following
recent
emigration,
also
appear
to
be
affected
by
AIDS,
as
may
a
small
number
of
persons
visiting
these
areas.
The
first
groups
form
a
pattern
strongly
reminiscent
of
hepatitis
B
infection
and
imply
an
infectious
aetiology
with
an
organism
that
is
transmitted
by
sexual
(especially
homosexual)
contact
or
blood
inoculation.
Other
lines
of
evidence
support
an
infectious
aetiology,
the
epidemic
rise
in
cases
and
in
particular
the
occurrence
of
sexually
associated
case
clusters,
including
a
notable
group
of
48
(Auerbach
et
al.,
1984).
The
early
epidemiological
association
of
AIDS
with
'fast
lane'
homosexual
life
styles
involving
large
numbers
of
sexual
partners,
especially
with
those
participating
in
multiple
anonymous
bathhouse
contacts,
could
be
most
readily
accounted
for
by
the
increased
chance
of
exposure
of
such
individuals
to
any
new
agent
appearing
in
the
homosexual
community.
Currently
individuals
with
lower
numbers
of
partners
are
increasingly
being
affected,
probably
indicating
a
greater
prevalence
of
the
agent
in
the
communities.
For
individual
patients,
the
number
of
sexual
partners
may
be
quite
small
(but
presumably
including
an
infected
partner).
The
predilection
for
certain
areas
of
New
York,
San
Francisco
and
Los
Angeles
could
be
explained
on
the
basis
of
the
congregation
of
homosexuals
with
the
most
'active'
life
styles.
The
geographical
dissociation
of
the
haemophiliac
cases
(Davis
et
al.,
1983;
Poon
et
al.,
1983;
Elliott
et
al.,
1983)
but
their
temporal
association
with
the
AIDS
epidemic
suggest
that
this
is
indeed
the
same
disorder
but
transmitted
differently:
by
blood
products,
probably
Factor
VIII
concentrate,
which
is
pooled
from
large
donor
numbers
(at
least
2,000)
and
transported
to
disparate
geographical
locations.
The
rare
blood
transfusion
associated
cases
suggest
such
a
link
too,
as
most
of
such
cases
affect
subjects
having
blood
from
many
donors;
for
example,
one
of
19
blood
donors
for
a
child
with
rhesus
disease
who
developed
an
AIDS
like
illness,
himself
later
developed
AIDS
(Ammann
et
al.,
1983a).
In
intravenous
drug
abuse
shared,
blood
contaminated,
needles
are
the
likely
mode
of
spread
and
there
are,
perhaps
for
this
reason,
concentrations
of
such
cases
in
particular
areas
(e.g.
the
Bronx
in
New
York).
Most
mothers
of
affected
children
(O'Reilly
et
al.,
1982)
with
AIDS
have
been
drug
abusers
(or
Haitians),
but
transmission
here
is
probably
at
or
around
the
time of
delivery,
as
with
hepatitis
B.
Affected
heterosexual
partners
of
AIDS
patients
(Masur
et
al.,
1982;
Harris
et
al.,
1983)
have
also
included
a
preponderance
of
drug
abusers
as
the
possible
source,
so
that
accidental
blood
inoculation
could
be
the
vector.
However
heterosexual
contact
alone
could
have
been
responsible;
some
female
prostitutes
have
been
affected
(Wallace
et
al.,
1983).
Contrary
to
earlier
ideas,
Haiti
may
well
have
acquired
AIDS
from
the
USA
as
it
emerged
at
a
similar
time
(Malebranche
et
al.,
1983;
Pape
et
al.,
1983;
Leonidas
&
Hyppolite,
1983).
Haiti
is
a
common
holiday
spot
for
American
homosexuals.
It
is
probable
that
sexual
contact
between
American
homosexuals
and
effectively
bisexual
or
homosexual
Haitians
may
have
led
to
its
appearance
in
Haiti
(where
the
male
to
female
ratio
of
AIDS
cases
is
high);
spread
to
heterosexual
partners
could
then
account
for
female
Haitian
cases.
Taboos
about
homosexuality
and
differing
perception
of
the
term
may
prevent
realistic
data
being
acquired
on
this
point
although
recent
studies
have
been
more
explicit.
Cases
linked
with
Central
Africa
go
back
further
(1976).
However,
the
well
recognized
endemic
Kaposi's
sarcoma
in
Africa
could
be
part
of
the
same
disease
spectrum
and
may
have
similar
transmission
characteristics,
as
judged by
the
epidemiological
features
together
with
anthropological
data
(Weber,
1984).
The
opportunist
infection
end
of
the
spectrum
could
easily
have
been
missed
in
this
setting.
There
is
some
suggestion
that,
within
African
countries
too,
the
recent
spread
is
of
epidemic
proportions.
Evidence
collated
from
several
sources,
particularly
imprisoned
intravenous
drug
abusers
(Wormser
et
al.,
1983)
and
transfusion
associated
cases
(Andreani
et
al.,
1983),
indicate
that
the
latent
period
from
the
time
of
putative
infection
to
declared
immunodeficiency
is
between
4
months
and
4
years.
Discrete
episodes
of
homosexual
activity
in
high
risk
areas
imply
a
similar
figure
for
sexually
acquired
disease.
However,
the
size
of
the
inoculum,
the
number
of
exposures,
the
route
of
exposure
and
host
factors
may
all
play
a
part.
It
is
important
to
recognise
that
cofactors
could
play
a
role
both
in
the
development
of
disease
and
in
its
manifestations.
Recreational
drugs
(especially
nitrites)
in
homosexuals,
other
contamina-
tion
of
needles
in
drug
addicts,
malnutrition
in
Haitians,
malaria
or
other
insect
borne
factors
in
the
tropics,
immunological
immaturity
in
neonates
have
all
been
proposed
but
more
evidence
is
needed
to
establish
their
role.
Genetic
predisposition
plays
a
part
in
determining
which
secondary
disease
emerges
(HLA
DR5
in
Kaposi's
sarcoma),
as
may
the
rate
of
onset
or
depth
of
immunosuppressive
effect.
This
may
explain
the
higher
rates
for
Kaposi's
in
homosexuals
as
compared
with
drug
addicts
for
example.
Haemophiliacs
may
not
develop
Kaposi's
because
of
their
genetic
background.
IMMUNOLOGICAL
FEATURES
The
central
evidence
of
cellular
immunodeficiency
in
AIDS
is
the
pattern
of
opportunist
disease
in
patients.
In
those
with
opportunist
infection
the
depth
of
immunodeficiency
judged
clinically
is
considerable,
with
negligible
evidence
of
host
response;
in
patients
with
opportunist
tumours,
it
appears
less
pronounced
and
prognosis
is
correspondingly
better.
The
laboratory
evidence
on
defective
cellular
immunity
in
large
part
supports
that
derived
from
the
clinical
picture:
patients
with
opportunist
infections
show
more
severely
disordered
immune
function
in
vitro
than
those
with
tumours.
Most
studies
have
included
data
on
T
lymphocyte
subsets
and
many
have
included
data
on
proliferative
responses
to
lectin,
antigen
and/or
alloantigen
(Gottlieb
et
al.,
1981,
1983;
Masur
et
al.,
1981;
Siegal
et
al.,
1981;
Mildvan
et
al.,
1982a;
Friedman-Kien
et
al.,
1982;
Wormser
et
al.,
1983;
Poon
et
al.,
1983;
Elliott
et
al.,
1983;
Vieira
et
al.,
1983;
Pitchenik
et
al.,
1983;
Malebranche
et
al.,
1983;
Schroff
et
al.,
1983b;
Ammann
et
al.,
1983,
Rogers
et
al.,
1983).
Lymphopenia
(T
A.
J.
Pinching
4
The
acquired
immune
deficiency
syndrome
lymphopenia)
is
universal
in
AIDS
with
infection,
and
relative
or
absolute
lymphopenia
is
seen
with
Kaposi's
sarcoma.
Characteristically
it
is
cells
of
the
T
'helper'
phenotype
(Th:
OKT4,
Leu
3a)
that
are
specifically
depleted.
Cells
of
the
T
'suppressor/cytotoxic'
phenotype
(Ts:
OKT8,
Leu
2a)
are
little
changed.
Unfortunately
much
data
has
been
presented
as
decreased
T
helper/T
suppressor
(Th/Ts)
ratios.
In
the
context
of
lymphopenia
(as
in
AIDS
cases)
a
decreased
Th/Ts
ratio
indicates
Th
depletion
and
Th
depletion
appears
to
be
a
good
marker
for
AIDS.
When
translated
to
the
setting
of
individuals
who
may
have
a
normal
lymphocyte
count,
especially
in
asymptomatic
members
of
'at
risk'
groups
or
in
putative
precursor
syndromes,
the
Th/Ts
ratio
becomes
a
meaningless,
and
indeed
misleading,
formulation,
as
it
may
conceal
two
quite
different
patterns
of
abnormality:
Th
depletion
or
Ts
increase.
The
latter
may
be
seen
following
a
number
of
infections
that
are
probably
irrelevant
to
the
causation
of
AIDS
but
which
are
common
in
the
at
risk
groups.
There
is
no
biological
reason
to
link
these
two
patterns
together
in
a
ratio.
Many
non-immunolo-
gists
involved
in
AIDS
work,
for
whom
the
ratio
may
have
been
an
attractive
simplification,
have
also
failed
to
appreciate
that
the
phenotypic
descriptions
'helper'
and
'suppressor'
cannot
be
translated
directly
into
functional
terms.
Indeed
it
is
increasingly
evident
that
the
surface
markers
tell
us
more
about
the
'languages'
that
lymphocytes
speak
than
about
the
work
they
do
(Reinherz,
Meuer
&
Schlossman,
1983).
Finally
one
should
exercise
caution
in
ascribing
functional
implications
to
tests
on
peripheral
blood
without
taking
account
of
the
behaviour
and
distribution
of
cells
in
lymphoid
and
other
tissues.
In
AIDS
the
pattern
in
tissues
however
appears
to
resemble
that
seen
in
peripheral
blood
(Cochran
et
al.,
1983;
Venet
et
al.,
1983).
Assays
of
T
cell
function
in
vitro
using
mixed
cell
populations
derived
from
patients
show
decreased
transformation
responses
to
antigen,
alloantigen
and
to
lectins.
These
broadly
match
the
altered
representation
of
lymphocyte
subpopulations.
Among
lectins,
phytohaemagglutinin
responses
are
reduced
but
pokeweed
mitogen
(PWM)
responses
are
more
affected
(Lane
et
al.,
1983).
Using
phenotypically
defined
subpopulations
with
reconstitution
in
vitro,
evidence
has
been
produced
that
the
remaining
Th
cells
are
functionally
abnormal,
while
Ts
cells
are
unaffected
(Lane
et
al.,
1983).
Selection
of
Th
functional
subsets
or
intrinsic
defects
in
the
remaining
cells
are
possible
causes.
Although
humoral
immunity
was
initially
considered
to
be
intact,
immunoglobulins
show
a
polyclonal
increase
in
AIDS
patients.
The
PWM
defect
suggests
that
B
cells
may
also
be
affected
and
this
has
been
confirmed
by
studies
with
a
pure
B
cell
mitogen
(Staphylococcus
aureus
Cowan
strain
1).
Spontaneous
immunoglobulin
production
by
AIDS
lymphocytes
has
been
found
to
be
substantially
increased,
confirming
the
polyclonal
B
cell
activation.
However
capacity
to
produce
immunoglobulin
with
PWM
is
reduced,
indicating
a
decreased
pool
of
partially
activated
cells.
In
co-culture
experiments,
B
cells
from
AIDS
patients
produced
little
immunoglobulin
with
normal
T
cells,
emphasizing
an
intrinsic
B
cell
defect.
In
vivo
and
in
vitro
responses
to
neoantigen
are
negligible.
Thus
in
AIDS
polyclonal
B
cell
activation
and
failure
of
response
to
neoantigens
has
been
demonstrated
(Lane
et
al.,
1983).
This
data,
apart
from
its
scientific
value,
has
major
implications
for
the
interpretation
of
serological
tests
in
such
patients.
Delayed
type
cutaneous
hypersensitivity
responses
to
recall
antigens
are
defective
in
AIDS
and
are
an
almost
universal
finding
(Gottlieb
et
al.,
1981,
1983;
Siegal
et
al.,
1981;
Friedman-Kien
et
al.,
1982;
Wormser
et
al.,
1983;
Poon
et
al.,
1983;
Elliott
et
al.,
1983;
Pitchenik
et
al.,
1983;
Malebranche
et
al.,
1983;
Pape
et
al.,
1983).
The
anergy
parallels
the
failure
of
in
vitro
lymphocyte
responses.
Most
probably
it
reflects
a
failure
of
T
cells
involved
in
delayed
type
hypersensitivity
responses,
in
T
memory
cells,
or
in
co-operation
with
macrophages.
It
is
unlikely
to
be
a
failure
of
the
final
common
pathway
of
inflammatory
response,
which
all
the
evidence
suggests
is
intact.
Natural
killer
(NK)
cell
function
is
defective
in
AIDS
patients
as
judged
by
conventional
cytotoxic
assays
using
targets
such
as
K-562
cells
(Siegal
et
al.,
1981;
Poon
et
al.,
1983).
It
is
apparently
matched
by
a
decrease
in
cells
bearing
the
proposed
NK
cell
marker
(HNK
1,
Leu
7),
even
though
this
may
only
partially
characterize
the
functional
subpopulation.
There
are
some
grounds
for
thinking
that
the
NK
defect
is
the
background
to
the
development
of
opportunist
tumours.
Immune
surveillance
may
operate
for
such
tumours
through
these
interferon
(IFN)-
dependent
cells.
The
therapeutic
response
to
IFN
in
some
Kaposi's
sarcoma
patients
(Krown
et
al.,
1983a,
1983b)
(in
those
with
the
best
preserved
lymphocyte
numbers)
implies
that
IFN
may
be
5
boosting
the
numbers
and/or
function
of
the
remaining
cells
of
this
proposed
surveillance
system.
Monocyte
function
is
defective
in
AIDS,
both
in
random
locomotion
and
chemotaxis
and
in
phagocytosis
(Fc-dependent)
(Maurice,
Smith
&
Pinching,
1982,
Pinching
et
al.,
1983).
It
is
probable
that
the
function
of
the
tissue
macrophages
that
derive
from
them
is
also
abnormal.
This
may
be
an
intrinsic
defect
or
a
result
of
failure
of
T
cell-macrophage
co-operation.
Such
defects
are
implied
by
the
occurrence
of
infections
with
intracellular
pathogens
such
as
Toxoplasma,
mycobacteria
and
Salmonella
spp.
By
contrast
neutrophil
function
is
normal
and
there
appears
to
be
no
defect
in
complement
or
in
the
mediators
of
the
inflammatory
or
acute
phase
response.
Circulating
immune
complexes
may
be
detected.
Among
soluble
factors
involved
in
cellular
immune
responses,
abnormalities
have
been
described
in
molecules
involved
in
the
maturation
of
T
cells
(thymic
hormones)
or
in
the
regulation
of
immune
responses
(interleukins,
lymphokines
etc.).
Much
of
this
work
is
more
tentative
than
the
foregoing
and
its
significance
(cause
or
effect)
remains
to
be
established.
Of
the
thymic
factors
thought
to
be
relevant
to
the
maturation
of
T
cells,
thymulin
is
apparently
decreased
(Dardenne,
Bach
&
Safai,
1983),
while
a,-thymosin
is
increased
in
serum
(Hersh
et
al.,
1983).
An
alteration
in
end
organ
responsiveness
has
been
proposed
to
account
for
the
latter.
Thymic
dysplasia
with
loss
of
Hassall's
corpuscles
(Elie
et
al.,
1983)
provides
collateral
evidence
for
thymic
defects
in
AIDS.
Lx-IFN
levels
appear
to
be
generally
decreased
in
AIDS
but,
perhaps
more
characteristically,
there
are
raised
levels
of
an
acid
labile
cx-IFN
similar
to
that
found
in
SLE
(DeStephano
et
al.,
1982).
Alterations
in
interleukin
production
or
responsiveness
have
been
found.
In
particular,
the
production
of
interleukin-2
(IL-2),
normally
elaborated
by
Th
cells,
appears
to
be
reduced;
evidence
of
decreased
cell
responsiveness
to
exogenous
IL-2
has
also
been
provided.
Among
other
serum
tests,
elevated
levels
of
f2-microglobulin
have
been
noted
(Francioli
&
Clement,
1982;
Zolla-Pazner
et
al.,
1984).
An
HLA
association
between
DR5
and
Kaposi's
sarcoma,
but
not
apparently
with
opportunist
infection,
has
been
described
(Friedman-Kien
et
al.,
1982;
Pollack
et
al.,
1983).
This
same
association
is
reported
to
affect
all
other
epidemiological
groups
previously
known
to
be
at
risk
from
Kaposi's
and
indeed
it
may
account
for
its
high
prevalence
among
subjects
of
Mediterranean
or
Ashkenazy
Jewish
extraction,
in
whom
DR5
is
more
frequently
represented.
It
now
appears
that
the
association
between
Kaposi's
and
DR5
is
lost
if
Italian
and
Ashkenazy
Jewish
patients
are
excluded.
AETIOLOGY
AND
PATHOGENESIS
While
in
the
early
approaches
to
this
problem
the
focus
tended
to
be
on
aspects
of
male
homosexual
life
style,
the
subsequent
evidence
that
the
same
disorder
has
appeared
over
a
similar
time
scale
in
a
number
of
other
distinct
groups
has
led
to
rather
different
hypotheses.
Any
hypothesis
must
answer
why
AIDS
has
arisen
now,
must
provide
an
explanation
for
its
exponential
increase
and
should
account
for
its
appearance
in
several
disparate
subgroups.
Occam's
razor
must
be
applied.
A
new
disease
with
an
exponential
rise
(not
accounted
for
by
ascertainment)
strongly
suggests
an
infectious
disease
and
the
evidence
for
this
has
been
considered
under
epidemiology
above.
A
hypothesis
can
be
constructed
which
fits
the
above
criteria
by
postulating
a
single
causative
agent
for
the
underlying
immune
deficiency,
an
agent
that
may
be
transmitted
(like
hepatitis
B)
by
homosexual
contact
and
by
blood
products.
The
homosexual
predominance
may
be
because
anorectal
intercourse
allows
an
agent
present
in
seminal
fluid
either
to
enter
through
intact
mucosa
or
through
small
mucosal
tears
direct
into
the
blood.
The
fewer
female
and
male
heterosexual
cases
could
be
due
to
non-sexual
spread,
or
could
result
from
anal
intercourse
in
the
female.
However,
numbers
of
sexual
contacts
are
smaller
among
heterosexuals
than
homosexuals
and
exposure
to
the
AIDS
agent
in
this
group
to
date
may
have
been
substantially
less,
so
it
is
possible
that
AIDS
can
be
transmitted
by
normal
heterosexual
intercourse.
Does
this
hypothesis,
which
is
now
the
most
widely
accepted,
stand
up
to
analysis
in
the
light
of
other
aspects
of
the
epidemic?
The
probable
increasing
prevalence
in
the
at
risk
communities
of
the
agent
could
explain
the
tendency
for
a
decrease
in
the
number
of
sexual
contacts
(epidemiologically)
of
current
AIDS
patients.
The
epidemiological
association
with
recreational
drug
(nitrites,
etc)
6
A.
J.
Pinching
The
acquired
immune
deficiency
syndrome
usage
(Marmor
et
al.,
1982)
and
with
certain
'fast
lane'
styles
of
sexual
activity
('fisting',
'rimming')
(Jaffe
et
al.,
1983),
may
prove
to
be
solely
a
link
with
increased
likelihood
of
exposure
to
infected
individuals,
although
some
of
these
factors
could
enhance
transmissibility
or
act
as
cofactors.
Excluding
for
the
moment
cases
from
Haiti
or
Central
Africa,
the
number
of
cases
not
fitting
into
the
above
at
risk
groups
is
very
small;
when
cases
without
adequate
information
and
those
inadvertently
included
in
the
epidemiological
definition
are
excluded
from
the
current
figures,
only
about
40
of
2,700
cases
are
unaccounted
for
(Curran,
1984).
This
strongly
suggests
that
other
routes
of
transmission
are
not
important,
unless
a
very
much
longer
incubation
period
applies
to
those
infected
by
other
routes.
The
major
group
that
has
not
been
affected,
and
which
that
might
be
expected
from
hepatitis
B
analogy,
is
health
care
workers,
especially
nurses,
doctors
and
laboratory
staff.
No
direct
spread
can
be
seen
to
this
group,
either
because
of
improved
standards
in
the
wake
of
hepatitis
B,
or
because
a
large
or
repeated
inoculum
is
required.
None
of
the
many
persons
suffering
inoculation
injury
have
developed
disease.
According
to
the
single
infective
agent
hypothesis,
the
causative
agent
must
be
new,
at
least
to
Western
countries.
Either
it
is
a
truely
novel
agent,
perhaps
acquired
from
another
human
reservoir
or
as
a
zoonosis;
alternatively
it
could
be
a
familiar
agent
which
has
changed
its
properties,
either
by
mutation
or
by
some
cofactor.
In
seeking
the
agent
in
AIDS
patients
there
are
many
problems
and
pitfalls.
If
found,
is
it
the
AIDS
agent
or
an
opportunist?
Is
it
an
agent
transmitted
in
a
similar
way
and
thus
a
marker
for
exposure
to
similarly
transmitted
agents?
Serological
evidence
may
be
obscured
by
polyclonal
B
cell
activation
with
increased
titres
of
antibodies
to
previously
encountered
antigens,
and
no
response
to
neoantigens
(perhaps
including
the
agent
itself)
(Lane
et
al.,
1983).
Cell
associated
agents
may
be
hard
to
find
in
late
stage
disease
when
the
infected
cells
may
have
been
largely
eliminated.
Ideally
a
particular
agent
should
be
present
in
all
patients
and
all
groups
(among
whom
potentially
confounding
factors
may
not
be
shared).
However
it
is
likely
that
an
agent
would
be
more
readily
discovered
early
in
the
disorder
before
secondary
disease
develops.
Unfortunately
however,
we
are
not
yet
able
to
define
reliably
subjects
in
a
precursor
or
latent
phase
of
the
disease.
If
such
an
agent
exists,
then
is
AIDS
the
only
manifestation?
Are
some
individuals
being
exposed
to
the
agent
and
eliminating
it
or
developing
mild
or
subclinical
disease?
It
is
certainly
possible
that
AIDS
is
only
the
most
severe
form
of
the
disease
caused
by
the
agent,
either
requiring
cofactors
or
massive/repeated
exposure.
Among
the
agents
that
are
known
that
have
been
proposed
as
the
aetiological
agent
of
AIDS
and
for
which
some
evidence
has
been
adduced,
are
CMV
(Gottlieb
et
al.,
1981),
hepatitis
B
(McDonald,
Hamilton
&
Durak,
1983;
Ravenholt,
1983),
EB
virus
and
human
T
cell
leukaemia
virus
(Essex
et
al.,
1983;
Gelmann
et
al.,
1983;
Gallo
et
al.,
1983)
fall
are
apparently
prevalent
among
AIDS
patients
to
varying
degrees.
CMV
is
a
strong
candidate
because
it
is
so
frequently
found
in
reactivated
form
in
AIDS
patients
and
is
known
to
be
(mildly)
immunosuppressive;
a
new
strain
is
a
possibility.
Hepatitis
B
is
also
prevalent
among
the
affected
persons
but
is
certainly
not
universal
on
the
basis
of
antibody
and
antigen
tests;
it
has
been
suggested
that
its
pathogenicity
could
have
been
altered
by
a
delta
like
agent
(McDonald
et
al.,
1983).
Human
T
cell
leukaemia
virus
(HTLV)
is
especially
attractive
as
an
agent
as
it
is
a
retrovirus
with
known
tropism
for
T
helper
phenotype
cells.
In
AIDS
it
could
be
causing
cell
destruction
rather
than
malignant
proliferation,
an
idea
not
without
precedent.
The
evidence
for
this
agent
in
AIDS
patients
is
not
entirely
satisfactory
and
while
viral
genetic
material
has
been
found
in
cells
from
a
few
AIDS
patients
(Gellmann
et
al.,
1983;
Gallo
et
al.,
1983),
the
only
evidence
of
high
prevalence
of
the
virus
in
affected
subjects
is
based
on
an
assay
of
uncertain
specificity
applied
at
the
limits
of
its
sensitivity
(Essex
et
al.,
1983).
Another
retrovirus
has
been
identified
in
France
(Barre
Sinoussi
et
al.,
1983)
but
its
broader
relevance
remains
uncertain.
A
significant
number
of
AIDS
patients
lack
evidence
for
each
of
these
agents,
suggesting
on
balance
that
none
is
a
common
factor;
they
are
all
similarly
transmitted
and
are
thus
likely
to
be
passenger
agents.
No
evidence
has
been
found
for
the
fanciful
suggestion
that
African
swine
fever
virus
is
responsible.
If
AIDS
is
indeed
due
to
a
viral
agent,
then
it
has
probably
not
yet
been
identified.
A
number
of
alternative
hypotheses
have
been
put
forward
which
merit
consideration.
The
idea
that
recreational
drugs,
especially
nitrites,
might
be
immunosuppressive
has
now
been
largely
abandoned
for
lack
of
evidence;
the
correlation
epidemiologically
appears
to
be
with
life
style.
The
idea
that
multiple
(sexually
transmitted)
infections
somehow
wear
down
the
7
8
A.
J.
Pinching
immune
system
never
seem
very
attractive
on
basic
principles.
An
alternative
is
the
idea
that
repeated
infection
over
long
periods
with
viral
agents
able
to
replicate
in
the
host
could
lead
to
a
summation
of
immunosuppressive
effects.
Increasing
numbers
of
patients
lack
evidence
of
such
a
process
prior
to
developing
AIDS.
Another
interesting
possibility
is
that
soluble
factors
derived
from
colonizing
gut
organisms
(e.g.
amoebae,
fungi)
could
be
immunosuppressive
(Pearce,
1983;
Sell
et
al.,
1983).
Tentative
evidence
has
been
adduced
for
the
release
of
a
cyclosporin
like
material
from
a
colonizing
or
infecting
fungus
(Sell
et
al.,
1983);
the
basis
for
this
colonization
or
infection
would
need
to
be
established.
Another
line
of
reasoning
has
emphasized
the
immunosuppressive
properties
of
seminal
fluid,
possibly
related
to
the
allogenicity
of
la
bearing
cells
in
seminal
fluid
(Shearer,
1983).
The
theory
rests
on
a
means
of
access
of
such
cells
via
rectal
mucosa
and
evidence
from
animals
injected
with
seminal
fluid
intravenously.
The
hypothesis
fails
to
provide
convincing
explanation
of
the
newness
of
the
syndrome,
its
epidemic
behaviour
and
its
simultaneous
appearance
in
other
and
diverse
groups.
By
the
time
that
AIDS
develops
clinically,
the
immunodeficiency
is
fully
evolved
and
may
have
some
immunological
features
that
are
secondary
to
deficiency
or
its
consequent
diseases.
It
is
hard
therefore
to
deduce
pathogenetic
mechanisms
without
stronger
evidence
concerning
early
events;
these
may
become
apparent
when
precursor
syndromes
are
better
defined
and
their
relevance
to
AIDS
better
established.
The
depletion
of
T
helper
phenotype
cells
is
a
notable
common
feature
in
AIDS
and
shows
appropriate
variation
in
degree
with
the
clinical
severity
of
immunosuppression;
the
T
helper
cells
that
remain
appear
functionally
defective.
This
evidence
favours
a
mechanism
operating
through
this
cell
type.
Although
decreased
natural
killer
cell
activity
is
another
major
feature
it
lacks
specificity
and
is
unlikely
to
be
primary.
Polyclonal
B
cell
activation
appears
to
be
an
early
event,
but
again
may
denote
a
non-specific
response
to
viral
or
other
infection.
Defects
in
monocyte
and
macrophage
function
are
apparent
in
vitro
and
are
implicit
in
the
development
of
infection
with
intracellular
pathogens;
it
is
not
clear
whether
these
are
primary
defects
or
simply
reflect
failure
of
T
cell-macrophage
co-operation
through
the
T
helper
cell
lack.
Alterations
in
thymic
structure
and
hormones,
in
interferons
and
interleukins
are
hard
to
evaluate
as
primary
or
secondary
events.
The
definition
of
the
causative
agent
and
the
reliable
delineation
or
precursor
syndromes
will
greatly
facilitate
the
search
for
pathogenetic
mechanisms.
THERAPY
IN
AIDS
Therapy
in
AIDS
must
be
divided
into
therapy
for
the
underlying
immunodeficiency
and
that
directed
at
secondary
diseases.
The
treatment
of
opportunist
infections
has
largely
been
established
in
other
immunosuppressed
states
and
a
number
of
these
infectious
agents
are
potentially
treatable
in
the
compromized
host
(e.g.
pneumocystis,
Candida,
Toxoplasma,
Cryptococcus,
Salmonella,
Herpes
simplex
virus).
Treatment
regimes
established
in
other
settings
may
also
be
effective
in
AIDS
but
treatment
failures
are
more
frequent.
In
some
cases,
apparently
effective
antibiotics
(in
vitro)
are
quite
ineffective
in
vivo
due
to
failure
of
host
response.
Cytotoxic
therapy
for
tumours
cannot
be
readily
transferred
from
other
settings.
Patients
with
Kaposi's
Sarcoma
have
the
best
prognosis
in
AIDS
and
even
a
modest
myelo
or
immunosuppres-
sive
effect
of
chemotherapy
could
tip
them
into
being
susceptible
to
opportunist
infections
with
a
correspondingly
worse
prognosis.
In
Kaposi's,
the
use
of
cloned
oc-IFN
in
high
dosage
is
both
logical
and
effective
(Krown
et
al.,
1983a,
1983b).
Its
use
stems
in
part
from
the
idea
that
NK
cells,
which
are
IFN-dependent,
are
involved
in
immune
surveillance
against
opportunist
tumours
like
Kaposi's.
Cessation
of
therapeutic
immunosuppression
in
renal
transplant
patients
following
the
development
of
Kaposi's
sarcoma
is
frequently
followed
by
tumour
regression.
It
may
be
that
the
40%
response
rate
of
Kaposi's
in
AIDS
(complete
or
partial
remissions)
reflects
a
comparable
immunorestoration.
The
benefit
appears
to
be
largely
restricted
to
those
subjects
in
whom
immunity
is
best
preserved
(higher
lymphocyte
counts
etc.)
and
is
thus
probably
stimulating
what
remains.
Interferon
does
not
appear
to
be
effective
in
treatment
of
opportunist
infection
in
AIDS.
Many
other
approaches
have
been
attempted
in
the
course
of
seeking
effective
therapy
for
the
underlying
immunodeficiency.
Transfer
factor,
thymic
factors,
thymic
transplantation,
white
cell
The
acquired
immune
deficiency
syndrome
transfusions,
bone
marrow
transplantation,
all
of
which
might
have
seemed
logical,
have
been
disappointing
in
achieving
clinical
benefit
in
full
blown
AIDS.
The
failure
of
bone
marrow
grafting
(the
treatment
of
choice
in
SCID
in
children)
is
especially
pertinent;
failure
despite
successful
engraftment
may
reflect
infection
of
the
new
cells
with
the
AIDS
agent
(Hassett
et
al.,
1983).
Clinical
trials
of
IL-2,
which
has
shown
encouraging
improvements
when
used
in
vitro
in
terms
of
NK
cell
and
CMV
specific
cytotoxicity
(Rook
et
al.,
1983),
are
not
yet
fully
evaluable,
but
are
not
encouraging.
The
lack
of
progress
with
such
therapy
may
be
a
genuine
failure
to
correct
the
basic
defect
or
to
avert
reinfection
of
immunocompetent
cells
within
the
host.
Alternatively
it
may
be
that
the
measures
have
been
introduced
too
late.
Again,
if
precursor
syndromes
can
be
reliably
identified,
it
seems
likely
that
appropriate
measures
could
prevent
the
progressive
attrition
of
immunocompe-
tence.
POSSIBLE
PRECURSOR
STATES
AND
SCREENING
The
importance
of
defining
immunodeficient
individuals
or
those
infected
with
the
AIDS
agent
before
they
reach
a
stage
of
clinically
apparant
immunodeficiency
has
already
been
stressed.
The
first
proposed
precursor
syndrome
was
that
of
persistent
unexplained
lymphadenopathy
(Mildvan
et
al.,
1982b;
Enlow
et
al.,
1983;
Metroka
et
al.,
1983;
Ragni
et
al.,
1983).
The
apparent
increase
in
this
clinical
presentation
at
the
same
time
as
AIDS
and
in
many
of
the
same
at
risk
groups
suggested
a
link.
Some
patients
with
AIDS,
especially
those
with
Kaposi's,
have
prior
lymphadenopathy.
Some
patients
with
unexplained
lymphadenopathy
have
subsequently
developed
AIDS.
However,
as
currently
defined
(generalized
lymphadenopathy,
lasting
for
more
than
3
months,
with
biopsy
showing
reactive
hyperplasia
and
not
shown
to
be
due
to
another
cause)
it
is
clear
that
it
is
potentially
very
heterogeneous.
Individuals
in
high
risk
groups
for
AIDS
have
a
high
incidence
of
unrelated
disorders
that
may
cause
lymphadenopathy.
In
studies
in
New
York
19%
have
progressed
to
AIDS
in
30
months
of
follow-up
(Mildvan
&
Mathur,
1984),
while
a
West
Coast
group
has
reported
a
1%
progression
in
2
years
(Abrams,
Lewis
&
Volberding,
1984).
These
discrepancies
may
reflect
different
definitions
and
exclusions,
or
differing
stages
of
the
epidemic.
They
indicate
the
heterogeneity
and
hence
lack
of
reliability
of
this
loose
definition
as
a
precursor
state.
In
New
York,
lymphadenopathy
patients
have
the
same
HLA
DR5
association
as
with
Kaposi's
(Enlow
et
al.,
1983).
The
group
as
a
whole
tends
to
show
similar
immune
abnormalities
as
AIDS
qualitatively
but
they
are
less
severe
(Mildvan
et
al.,
1982b;
Stahl
et
al.,
1982;
Wallace
et
al.,
1982).
However,
some
of
this
rests
on
the
use
of
Th/Ts
ratios
and
may
include
some
cases
with
the
apparently
unrelated
Ts
increase.
Even
if
related
to
AIDS,
some
cases
may
be
formes
frustes
that
need
not
progress.
Lymph
node
histology
(Fernandez
et
al.,
1983;
Metroka
et
al.,
1983)
and
immunohistology
indicate
some
heterogeneity
but
longitudinal
studies
are
needed.
Other
prodromal
symptoms
have
been
noted
including
unexplained
weight
loss,
malaise,
fatigue,
diarrhoea
and
oral
candidiasis
(Mildvan
&
Mathur,
1984).
While
some
may
be
due
to
undiagnosed
opportunist
infection,
others
may
represent
a
definite
precursor
syndrome.
Some
groups
are
now
using
a
term
'AIDS
related
complex'
to
describe
a
combination
of
some
of
a
number
of
such
clinical
and
AIDS
like
laboratory
features,
which
may
be
more
clearly
predictive
of
the
development
of
AIDS
over
a
rather
shorter
time
span
(77%
progression
written
4
months
according
to
one
group;
Mildvan
&
Mathur,
1984).
An
alternative
approach
is
to
seek
laboratory
evidence
of
AIDS
like
immune
defects
in
asymptomatic
members
of
at
risk
groups
(Goedert
et
al.,
1982;
Stahl
et
al.,
1982;
Kornfeld
et
al.,
1982;
Wallace
et
al.,
1982;
Detels
et
al.,
1982;
Fahey,
Detels
&
Gottlieb,
1983;
Pinching
et
al.,
1983,
1984;
Lederman
et
al.,
1983;
Menitove
et
al.,
1983;
Goldsmith
et
al.,
1983;
Luban,
Kelleber
&
Reaman,
1983).
However
this
involves
applying
non-specific
tests
that
are
insufficiently
validated
outside
defined
clinical
settings.
Among
other
things,
the
high
background
of
other
(non-AIDS
related)
intercurrent
illnesses
which
may
affect
such
tests
that
are
seen
in
at
risk
subjects
make
interpretation
of
these
studies
extremely
difficult.
Furthermore
there
is
no
a
priori
reason
why
the
pattern
seen
in
full
blown
AIDS
will
necessarily
be
preceded
by
the
same
pattern
in
its
evolution.
The
predictive
value
of
lymphopenia,
Th
depletion,
Ts
increase,
Th/Ts
ratio
decrease,
decreased
9
Io
A.
J.
Pinching
a-IFN
(Lopez,
Fitzgerald
&
Siegal,
1984),
increased
acid
labile
a-IFN
(Eyster
et
al.,
1983)
increased
fl2-microglobulin
(Zolla
Pazner
et
al.,
1983),
increased
aI-thymosin
(Goldstein
&
Naylor,
1984),
etc,
all
await
validation
in
longitudinal
studies
in
terms
of
the
development
of
the
disease.
All
show
some
promise
on
the
basis
of
incidence
in
at
risk
groups.
Preliminary
results
of
such
longitudinal
studies
of
lymphocyte
subpopulations
have
shown
that
not
only
does
Ts
increase
(associated
with
prior
viral
infections)
frequently
revert
to
normal,
but
some
instances
of
Th
decrease
may
also
improve
spontaneously
(Marmor
et
al.,
1984;
Pinching
et
al.,
1984).
A
heterogeneity
of
causes
for
such
patterns
is
thus
likely
and
interpretation
should
be
guarded
at
this
stage.
Careful
prospective
studies
will
however
provide
valuable
information
on
others
may
clarify
the
background
events
occurring
in
these
subpopulations.
Only
by
such
studies
may
the
early
phases
of
AIDS
be
recognized,
enabling
us
to
evaluate
aetiological
or
pathogenetic
hypotheses
and
therapeutic
approaches.
Intervention
to
stem
the
epidemic
of
AIDS
is
most
likely
to
arise
from
knowledge
obtained
in
this
way.
CONCLUSIONS
A
novel
epidemic
form
of
acquired
immunodeficiency
has
arisen
in
distinct
subsections
of
the
community.
In
5
years
it
has
justifiably
provoked
unprecedented
scientific
activity
as
well
as
intense
concern
amongst
the
public.
It
is
likely
that
our
comprehension
of
basic
mechanisms
of
immune
regulation
will
be
greatly
advanced
by
the
questions
posed
by
this
clinical
problem.
It
is
to
be
hoped
that
the
social
and
political
consequences
of
AIDS
will
be
as
positive.
I
am
grateful
to
my
many
colleagues
who
have
helped
me
to
reach
an
understanding
of
this
subject.
AJP
is
a
senior
lecturer
and
honorary
consultant
in
Clinical
Immunology
at
St
Mary's
Hospital.
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LEWIS,
B.J.
&
VOLBERDING,
P.A.
(1984)
Lymphadenopathy:
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prodrome-
update
of
a
24
month
prospective
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Ann.
N.
Y.
Acad.
Sci.
(in
press.)
AMMANN,
A.J.,
COWAN,
W.J.,
WARA,
D.W.,
WEIN-
TRUB,
D.,
DRITZ,
S.,
GOLDMAN,
H.
&
PERKINS,
H.A.
(1983a)
Acquired
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in
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A.J.,
ABRAMS,
D.,
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M.,
CHUDWIN,
D.,
COWAN,
M.,
VOLBERDING,
P.,
LEWIS,
B.
&
CASAVANT,
C.
(1983b)
Acquired
immune
dysfunc-
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in
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Clin.
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LE
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A.,
BROUET,
J.-C.,
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LACHANCE,
J.R.,
MESSING,
B.
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VERNISSE,
B.
(1983)
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by
Haitian
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Lancet,
i,
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P.J.
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(1982)
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