<<In what might be the most important treatment presentation at
the 12th World AIDS Conference>>
AEGIS] (ATN) HIV-Specific Immune Responses Restored by HIV
HIV-Specific Immune Responses Restored by HIV Immunogen
Plus Antiretroviral Suppression
John S. James
AIDS TREATMENT NEWS Issue #298, July 10, 1998
aegis.com
In what might be the most important treatment presentation at
the 12th World AIDS Conference (Geneva, June 28 - July 3), New
York University immunologist Fred Valentine, M.D., reported a
striking return of HIV-specific immune responses from a
multicenter controlled trial of REMUNE(TM) (the Salk HIV
treatment vaccine, being tested by the Immune Response
Corporation of Carlsbad, California, and Agouron
Pharmaceuticals, Inc., of La Jolla, California; see AIDS
TREATMENT NEWS #297)--in a 43-patient clinical trial where this
potential treatment, called the HIV immunogen, was given to
patients whose viral load had been very well suppressed by
conventional antiretroviral treatment(1).
In almost all viral infections, control of the disease is
associated with a very strong "lymphoproliferative response"
(LPR)--the ability of certain immune-system cells in the blood
to recognize the virus and then grow rapidly, producing many
more such cells, which then mobilize other immune-system cells
against the virus. With HIV infection, however, it has been
known for years that the LPR to HIV is largely absent at all
stages of disease--except for a small minority of patients, who
do have a strong LPR against many antigens of HIV. These
patients are always long-term nonprogressors, able to control
the virus for many years and perhaps indefinitely, without
treatment.
Dr. Valentine presented preliminary results of a controlled,
double-blind clinical trial at eight medical centers, which
clearly showed that lymphoproliferative responses like those of
long-term nonprogressors can be induced by treatment in
patients who otherwise would not have them. These responses
were seen against an unrelated strain of HIV (not only against
the HIV immunogen itself). Whether these induced responses are
helpful like those which develop naturally (earlier in
infection) will not be known until some patients stop their
antiretrovirals and see if, or how rapidly, their viral load
returns.
Background
The lymphoproliferative response, measured by a complex
laboratory test, is a major indicator of how well a person's
immune system responds to a particular antigen (an antigen
usually consists of peptides, short sequences of proteins,
produced by a particular virus, bacterium, or other disease-
causing organism), which the body's cells had already learned
to recognize through previous exposure. The lack of this
response to HIV (in most patients, except for long-term
nonprogressors) has been a central mystery of this disease.
(Interestingly, chimpanzees--which can be infected with HIV but
seldom become ill--do have a strong LPR against HIV.)
The LPR is measured in the laboratory by culturing blood cells
from the patient in the presence of the antigen of interest
(here, HIV). Usually a small fraction of CD4+ T- helper cells
will be able to recognize the particular antigen, and as a
result they will begin to reproduce rapidly. The amount of cell
growth in the whole cell culture can be measured by including
tritium, a radioactive form of hydrogen, in the growth medium,
in a form that will be picked up by and incorporated into
growing cells. Later, technicians separate the cells from the
remaining growth medium, and then they can easily measure how
much radioactivity the cells have.
The result of this test is given as a "stimulation index"--a
measure of how well that person's immune-system cells respond
to the antigen being tested. The stimulation index is the ratio
of how much radioactivity is present in cells from a culture
which included the antigen, vs. cells in a control culture
which was treated the same except that the antigen was not
added.
For example, the stimulation index of an HIV-negative person
who has been infected with CMV will often be in the range of
five to 50--meaning that when their cells were exposed to the
CMV antigen, a few recognized it and grew enough that the
culture as a whole took up five times to 50 times as much
tritium as the cell culture not exposed to the antigen. The
stimulation index can be as large as 100 or more; or on the
low end of the scale, a stimulation index of one means no
response (and an index of two could also mean no response,
due to errors in the testing). Measuring the LPR is labor
intensive and requires highly skilled technicians in order to
assure accuracy; as a result, this test of immune function
has remained a research method and not become part of
standard clinical practice.
In patients with HIV (except for long-term nonprogressors)
the LPR to HIV is very weak or not present at all. The LPR to
CMV and other opportunistic pathogens with which the patient
has been infected may be lost later in late-stage HIV
disease--but if the HIV is then suppressed with
antiretrovirals, the LPR to the opportunistic infections will
often come back. But the LPR to HIV does not occur by itself,
even when the virus has been fully suppressed and has
remained undetectable for years.
Why does the immune system of most patients fail to produce a
lymphoproliferative response to HIV? No one knows for sure,
but the dominant theory today is that HIV may kill off the
small fraction of T-helper cells which are genetically able
to recognize it--since these cells become activated during
primary infection and therefore are vulnerable to being
infected and destroyed by this virus.
The lack of HIV-specific LPR might explain why viral load
usually returns quickly if antiretroviral drugs are stopped.
But in the few long-term nonprogressors, the body somehow
gets the upper hand instead, HIV-specific responses are
preserved, and the virus remains controlled without
treatment.
An excellent review of this area by Dr. Valentine and others
appeared just before the Geneva conference in a supplement to
the June issue of AIDS RESEARCH AND HUMAN RETROVIRUSES(2).
This article referred to the study which Dr. Valentine
presented in Geneva (described below); however, the data was
blinded when that publication went to press, meaning that the
authors did not know what patients had received the real HIV
immunogen and which had received a placebo. There was an
indication that the treatment was working, however:
"Although the study is still blinded, approximately one half
of the subjects have developed stimulation indices to the gag
protein of between 10 and 400... These stimulation indices
and those obtained by immunization with envelope vaccines
often are as large as those seen in long-term immunological
nonprogressors who develop proliferative responses as a
consequence of their initial encounter with the virus."
[Note: The gag protein is a "core" protein of HIV. It tends
to be more constant from strain to strain than the "envelope"
proteins found on the surface of the virus.]
The Geneva Report
In a 10-minute "late breaker" session, Dr. Valentine gave a
preliminary report of a 32-week clinical trial conducted at
eight research centers; this trial had been completed, but
only the first 20 weeks of data had been analyzed and were
available for the presentation. Forty three patients were all
given antiretroviral therapy (indinavir plus AZT plus 3TC).
Four weeks later, they were vaccinated with either the REMUNE
HIV immunogen, or a control vaccination. The active or
control immunization was repeated every three months.
The purpose of this study was to see if the
lymphoproliferative response could be induced by immunization
when a patient's viral load was well suppressed by
antiretroviral drugs; previous data had suggested that this
might be possible. Other measurements included viral load
(using an ultrasensitive test with a lower limit of 40
copies), CD4 counts, and the level of the chemokine MIP-1-
beta.
The REMUNE HIV immunogen--a vaccine-type treatment for
persons already infected with HIV, designed by the late Dr.
Jonas Salk and currently in a large phase III trial, is made
from whole killed HIV from which the gp 120 envelope protein
has been removed. It also contains an adjuvant (IFA, or
incomplete Freund's adjuvant); an adjuvant is used to make a
vaccine work better. The control vaccine used in this trial
consisted of the adjuvant alone.
According to a July 3 press release from New York University
Medical Center, the 43 patients had a median CD4 count of 493
and a median viral load of 8,159 copies before they began the
study.
The patients who received the HIV immunogen consistently
developed strong lymphoproliferative responses like those of
long-term nonprogressors; some of the volunteers who received
the immunogen had stimulation indices in the hundreds. Those
who received the control vaccination (adjuvant only, without
the killed HIV) had very low stimulation indices, usually
around three for envelope proteins and slightly higher for
gag. Dr. Valentine also noted data from long-term followup of
one of the Merck trials; patients who had been on the same
antiretroviral regimen and had their virus undetectable for
almost three years (but who had not received any HIV
immunization) had no spontaneous recovery of their
lymphoproliferative response.
The LPR was tested by using different antigens--not only from
the HIV immunogen itself, but also a recombinant p24, and
most importantly, a whole virus from clade B--a strain of HIV
very different from the one used to make the immunogen.
(Clade B is the form of HIV which is common in North America.
But Dr. Salk developed the immunogen using an early HIV
isolate from a woman in Zaire. This virus later was found to
be a natural recombinant, consisting of a clade A envelope
and a clade G gag protein. This cross-clade reactivity of the
immunogen (to the clade B virus) suggests that if this
treatment turns out to be useful, it could be applied to
different HIV strains in different parts of the world.
The immune response to a clade different from that of the
antigen which induced it is unusual--but not especially
surprising in this case, however, since this virus targets
the gag protein, which tends to be relatively similar among
different strains of HIV (the envelope differs much more, but
this part of the virus is stripped off when the immunogen is
made). The lymphoproliferative response recognizes peptides,
which are short fragments of proteins--and the peptides from
different viruses are often the same.
Comment
This very important study leaves many questions unanswered.
The most urgent is whether the patients who had
lymphoproliferative responses induced in this way will
benefit from it and perhaps become long-term nonprogressors.
While it seems logical that the answer is yes, it is also
possible that LPR is only a consequence or marker of a good
immune response which controls the virus by some other
mechanism; it might not be the cause of the viral control by
long-term nonprogressors.
Many scientists did not expect this treatment to work, since
these patients had already been exposed to plenty of HIV
antigens due to viral replication. A major question now is
why the additional exposure to antigens through the vaccine
was so much more effective.
What surprises us is how well the study worked--since it can
take months or years for naive cells to recover in an adult
after immunosuppression. If the cells able to recognize HIV
had indeed been wiped out, as the predominant theory
suggests, could the lymphoproliferative responses have come
back so strongly in only 16 weeks (from the four-week point
of first immunization, to the 20-week point which contributed
the last data available for presentation in Geneva)? If,
however, the cells had not been destroyed but had been turned
off or suppressed in some way, then it would be important to
learn how the HAART (highly active antiretroviral treatment)
plus immunogen reversed such an effect. Perhaps a more
specific treatment could produce the same result.
The volunteers in this trial were relatively early in HIV
disease progression, but well past the stage of primary
infection. No one knows how well the approach would work on
persons with more advanced illness. It is often best to avoid
the more difficult cases when first establishing a proof of
principle--and then improve the treatment and extend it to
more patients.
Since this study was presented in one of two simultaneous
late breaker sessions at the very end of the conference,
there was little time for discussion among attendees before
people went home. Part of the data (from the patients at the
New York University site alone) had been reported by Dr.
Valentine the day before, during a satellite session
organized by the Immune Response Corporation; about 400
people showed up for this 6:30 a.m. meeting.
Other Studies
A number of laboratory and animal studies relevant to
restoring HIV-specific immunity were also presented at the
12th World AIDS Conference; we were not able to review them
before going to press. Also, other human trials which may
restore these responses are either ongoing, or now being
organized.
References
1. Valentine FT, DeGruttola V, Kaplan M, and others. Effects
of HAART compared to HAART plus an inactivated HIV immunogen
on lymphocyte proliferative responses (LPR) to HIV antigens.
12th World AIDS Conference, Geneva, June 28 - July 3, 1998
[abstract # 31227 (late breaker session, #LB 9)].
2. Valentine FT, Paolino A, Saito A, and Holzman RS.
Lymphocyte-proliferative responses to HIV antigens as a
potential measure of immunological reconstitution in HIV
disease. AIDS RESEARCH AND HUMAN RETROVIRUSES June 1998;
volume 14, supplement 2, pages S-161 to S-166.
Copyright 1998 by John S. James. Permission granted for
noncommercial reproduction, provided that our address and phone
number are included if more than short quotations are used.
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