PI Perspective #26
December 1998 View PDF En
español
Interleukin-2 (IL-2):
A Path Toward Functional Eradication?
Recent research has demonstrated that antiviral drugs can be extremely
effective in reducing or practically eliminating all evidence of
HIV in the bloodstream and in actively replicating cells. However,
careful study shows that HIV infection persists despite this.
In one study, which included people treated with Highly Active
Anti-HIV Therapy (called HAART) very early after initial infection
with HIV, virus capable of reproducing was found in every individual
treated despite the fact their HIV levels were below the limit of
detection with currently available tests. The apparent cause of
this is the presence of a population of resting T-cells which are
infected by HIV. While in their resting state, the cells provide
a near perfect harbor for HIV. The immune system doesn’t recognize
them as infected cells because they aren’t expressing virus
or the surface markers that would indicate they are infected. The
immune system can only detect the presence of HIV when a cell is
actively producing new virus, which identifies the cell as infected.
Similarly, anti-HIV drugs can play no role with resting cells for
the same reason. Drugs can only interfere with the production of
new virus or the infection of new cells by active virus. Therefore,
they can’t do anything when the virus is resting inactive
inside a cell. These resting, or quiet cells, are believed to be
the major reservoir of HIV infection.
These cells can persist indefinitely, and virus lurking within
them can rekindle active HIV infection. When and if these cells
become active, they can begin producing virus. This reservoir of
resting cells is believed to be one of the major barriers to completely
eliminating HIV from a person’s body.
Researchers who are attempting to achieve eradication (e.g. the
complete elimination) of HIV are now planning to test different
methods of converting these resting T-cells into active cells. Once
activated, these cells should be vulnerable to the immune system
and to antiviral drugs, just like other cells. Interleukin-2 (IL-2
or Proleukin) stimulates resting cells, thus exposing both virus
and cells to the effects of anti-HIV drugs as well as the immune
response against HIV. Using IL-2 therapy may help to decrease or
eliminate this hidden pool of virus.
In August, Dr. Anthony Fauci, Director of the National Institute
of Allergy and Infectious Diseases (NIAID, the institute which funds
the majority of AIDS research efforts worldwide), presented new
findings from an exploratory study of IL-2 used in combination with
potent anti-HIV therapies.
At the International AIDS Conference in Geneva, Dr. Fauci and his
colleagues raised the question of whether people treated with HAART
plus IL-2 are any different from those treated with HAART alone.
Specifically, they wondered whether IL-2-treated patients would
have similar or different levels of the resting, infected T-cells
compared to people on HAART alone.
After Geneva, they conducted a study to answer this question. The
study compared two groups. The first consisted of 13 people with
viral load levels below the limit of detection for 6 months or more
using a very sensitive test (limit of detection 50 HIV RNA copies
per ml). All were participating in NIH studies of HAART and IL-2.
The second group recruited volunteers taking a HAART regimen for
6 months or longer and who had viral levels below the test’s
limit of detection. The two groups were very similar with regard
to baseline CD4+ cell counts and viral load, length of prior therapy
with HAART and other characteristics.
The research team then used sensitive tests to look for the presence
of HIV DNA inside resting T-cells capable of reproducing (replication
competent virus). Initially, they looked at about 10 million cells
per individual. This has been sufficient in other studies to find
infected cells and replication competent virus in virtually all
HIV-infected people. Replication competent virus was readily found
in resting cells in all 13 people who received HAART alone. In six
people who had received HAART in combination with IL-2, however,
the researchers could not detect replication competent HIV or latently
infected cells.
Five of the six individuals who had been receiving the IL-2-containing
regimen and had no detectable replication competent virus were studied
further. Even more sensitive tests were run by searching through
greater numbers of cells, more than 300 million cells from each
person. Despite this intensive unprecedented search for the virus,
researchers were still unable to find replication competent virus
in three of the five individuals. To make sure this wasn’t
a temporary phenomenon and recheck their accuracy, the tests were
repeated several weeks later in all six patients. The results were
nearly identical, except this time the researchers searched even
further, through more than 400 million cells, without finding HIV
in the same three people.
Although virus was not found when looking at more than 300 million
cells, it does not necessarily mean that virus has been completely
eliminated from these people. To make such a claim, Fauci said one
would technically have to examine every cell in the body, and no
one is likely to ever do that. An even more intensive search is
underway now looking for virus in deeper immune compartments, such
as the lymph tissue. The next step, underway now, is to sample lymph
tissue from the rectal mucosa and to examine spinal fluid.
The relevance of these observations might only be understood when
or if these few people choose to stop their anti-HIV therapy. If
there are still extremely small amounts of virus somewhere in the
body, stopping HAART might allow the virus to re-establish itself
and rekindle the fires of HIV disease. The real question is not
whether HIV is completely eradicated, but whether there is enough
of it still present to rekindle an active state of infection.
There is already some indication that full eradication is not necessary
to prevent recurrence of active infection. For example, more than
ten patients in the U.S. and Europe are currently being studied
who have already gone off therapy on their own choosing. Whenever
researchers have looked, these patients have measurable levels of
replication competent virus—unlike those in Fauci’s
new study. Yet these ten people have been off of all anti-HIV therapy
from 3–18 months without experiencing a return of measurable
viral load. Fauci’s patients would seem to have at least as
good a chance as these people of successfully stopping therapy.
Preliminary results from this study are extremely encouraging and
go beyond any data reported elsewhere. Still, another larger study
needs to be designed quickly to confirm the findings. While in laboratory
studies IL-2 appears to stimulate HIV replication, it may be that
when used with anti-HIV therapy, IL-2 may help flush the reservoir.
That in turn may expose virus to the effects of anti-HIV therapy
as well as the immune response against the virus and then ultimately
assist in more greatly decreasing the amount of HIV in the body.
IL-2 studies in people with HIV show that the therapy has the most
profound and dramatic impact on CD4+ cell count than any therapy
in the history of AIDS research. Numerous studies have confirmed
the ability of IL-2 to effect pronounced CD4+ cell increases over
and above what is realized with anti-HIV therapy alone. Thus far,
lab studies suggest that CD4+ cells increased as a result of IL-2
therapy appear just as normal and useful as cells generated after
successful HAART therapy.
It remains unclear if these increases will contribute to decreases
in the risk of developing HIV-related infections or prolonged survival,
though there seems to be no reason to expect otherwise. A study
to answer this question is being planned and will hopefully begin
to enroll early next year. A component of the trial, being conducted
through a community based clinical trial network (CPCRA), is currently
opening in sites throughout the U.S. For more information about
trial sites, call 1-800-TRIALS-A and ask for CPCRA IL-2 study sites
in your area.
Personal Decisions About IL-2 Therapy
While the growing bulk of results from IL-2 studies are increasingly
encouraging, those contemplating becoming involved in an IL-2 study
should be aware the therapy can be hard on patients. The most common
side effect associated with IL-2 is mild to severe flu-like symptoms.
Nearly everyone using IL-2 can expect to experience this side effect
during the time therapy is taken (e.g. the five-day course of IL-2).
IL-2 therapy is not taken every day. It is cycled and taken for
five days in a row, every eight weeks. Therapy is delivered through
injection directly under the skin (subcutaneous). Time between cycles
may be extended in IL-2 recipients who realize pronounced and prolonged
CD4+ cell increases.
In a recent report on the long-term follow up of people in a NIAID
study of IL-2, the average duration between cycles to maintain CD4+
cell counts at about 1,200 was one year. However, the individuals
in this study had very high CD4+ cell counts (about 600) to start.
This kind of immediate response is not expected among people who
initiate IL-2 with lower CD4+ cell counts, where increases may take
longer to realize. Sustaining those increases may require continued
and frequent dosing.
For more information on IL-2, read Project Inform’s publication,
IL-2.
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