PI Perspective #40
January 2006 View PDF En
español
Project Inform Analysis:
Results of a "Cure" Study
The August 12 2005 issue of The Lancet reported on the results
of a study which attempted to reduce the reservoir of cells that
are latently infected with HIV. In theory, a treatment that could
achieve this perfectly might result in an outright cure of HIV disease
since scientists believe it is the continued presence of this reservoir
that makes HIV infection a permanent condition. This study was one
of series of steps researchers have taken attempting to deal with
the problem of the reservoir of HIV-infected cells. Unfortunately,
the magazine splashed the word CURE all over its cover, raising
inappropriate expectations about what the study was able to accomplish.
These latently infected cells are normally not affected by anti-HIV
drugs because they are inactive and not producing virus. Thus, the
anti-HIV drugs have no effect on them. Most anti-HIV drugs only
work with cells that are active, HIV-infected and producing new
copies of virus. Additionally, when HIV-infected cells are inactive,
they are also not recognized by the immune system as a problem,
again because they are not producing virus or doing anything the
immune system recognizes as “wrong.” Thus, they “fly
under the radar” of the immune system and remain a constant,
unchecked threat. Any time the latently infected cell “wakes
up” or is activated, it begins producing new copies of HIV.
Thus, the body never rids itself of HIV. Some is always left in
reserve.
This particular approach to reducing the reservoir described in
The Lancet article was proposed and discussed in Project Inform’s
Immune Restoration Think Tank several years ago. It was proposed
at that time by Dr. David Margolis, whose lab managed the study
mentioned in The Lancet article. The general model of attempting
a “cure” in this fashion was in fact proposed by immunologist
Max Cooper of Alabama at the very first meeting of the Think Tank
back in 1991, when the meeting was hosted by the National Academy
of Science’s Institute of Medicine. Project Inform has described
this potential approach to a cure in a number of articles over the
years. For those wanting more background, consider the following
(available through Project Inform’s Hotline and website):
PI Perspective #26, 1998—Interleukin-2:
A Path Toward Functional Eradication?
PI Perspective #24, 1998—HIV
Eradication: Dead or Alive, or Even Necessary?
PI Perspective #19, 1996—Eradication
of HIV: Hope or Hype?
PI Perspective #17, 1995—Four
New Concepts for Combating HIV Infection
The basic idea of flushing the reservoir begins with providing
maximum suppression of viral replication by whatever means available.
This is to make sure that no new HIV is created in the body or allowed
to infect cells while the effort to clear the reservoir takes place.
In this case, the small study reported in The Lancet included four
people whose HIV levels were already “undetectable”
while on anti-HIV therapy. Their treatment was then intensified
with the addition of a potent new drug, T20 (enfuvirtide, Fuzeon).
Up to this point, Margolis’ approach was similar to earlier
efforts to rid the body of HIV. But his approach differed in the
next step. Earlier efforts by other researchers added another type
of drug that was intended to “activate” the latently
infected cells in the reservoirs. The hope was that this would make
the cells visible to the immune system as they began to produce
HIV, leading to their eventual death, while the standard anti-HIV
drugs blocked any new virus from infecting other cells. These past
approaches failed, either because the effort to activate the cells
proved too toxic, or because it failed to activate all the latently
infected cells.
Margolis’ team tried a different approach at this step. They
added a well known and quite safe anti-convulsive drug, valproic
acid, to the patients’ daily regimens. Recent research had
shown that the drug seemed to interfere with the process that allowed
some HIV-infected cells to become dormant in the first place. Those
cells that were already dormantly infected with HIV would just die
off on their own over time. If no new dormant, infected cells were
created, they theorized the chronic HIV infection would eventually
be eliminated.
The challenge of this or any approach to truly “curing”
the disease is that virtually every latently infected cell must
eventually die without a single new copy of virus being allowed
to infect another cell. That’s a pretty tall order and to
date, no one has even come close to achieving it.
In the study reported in the August issue of The Lancet, a reduction
of the number of latently infected cells, ranging from 68–85%
in three of the four volunteers, was observed, while there was no
response in the fourth volunteer. Researchers concluded that that
this could be proof of the concept that we might someday be able
to cure the disease. Dr. Margolis said that he was concerned that
people might over-interpret these results as meaning a cure had
been found, but he defended the belief that this was a step in that
direction. Some scientists and many people living with HIV applauded
the effort, while others raised caution because of the great challenge
of dealing with virtually every infected cell.
While Project Inform is a staunch believer in the possibility and
eventuality of a cure for AIDS, it’s not clear that it’s
going to happen through eradication schemes of this nature. Others
have done similar experiments, such as Roger Pomerantz at Thomas
Jefferson University. He had similar results and a few patients
remained virus free afterwards, without treatment, for several months.
But eventually virus levels returned to detectable, evidence that
not all infected cells were destroyed. Another similar experiment,
at the Aaron Diamond Research Center in New York, resulted in what
may have been life-threatening complications in a patient due to
the side effects of a high a dose of the drug (OKT3) used for activating
cells. Because the experiment failed and a patient was endangered,
this experiment did not continue. Researchers in Dr. Anthony Fauci’s
lab at the National Institute of Allergy and Infectious Diseases
also attempted eradication with a combination of anti-HIV drugs
and IL-2 (interleukin-2, Proleukin), a potent immune stimulator.
Although viral expression was completely suppressed in a number
of people, without further treatment, for a number of months, HIV
eventually reappeared. This proved that some latently infected cells
had escaped the process.
It was refreshing in this new case that some scientists were able
to see the results as a sign of progress rather than failure. Research
of this type should definitely continue, even it has not yet been
fully successful. It may be that multiple rounds of the process
need to be repeated to achieve success or a longer period of treatment.
Or perhaps we need to try a combination of activating the latently
infected cells plus the new approach demonstrated by Dr. Margolis.
One thing is clear though and it is that the mere use of standard
anti-HIV drugs is unlikely to cure AIDS. One way or another, the
problem of the reservoir of latently infected cells must be addressed.
We applaud Dr. Margolis and his team for continuing this kind of
research, even if we feel The Lancet may have engaged in a bit of
unhelpful hype on the magazine’s cover.
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