Being Alive 1994 Jan 5: 3
Dr. Anthony Fauci is Director of the National Institute of Allergies
and Infectious Disease (NIAID), the branch of the National Institutes
of Health (NIH) most directly responsible for AIDS research. While he
is a hero to some and a bureaucratic villain to others, he is
indisputably a leading immunologist. He directs his own AIDS research
laboratory and, because of his stature and power, helps frame the ever
changing debate on the complex nature and causes of AIDS-related
Those who regularly attend AIDS scientific meetings have grown a bit
weary of his standard speech which has varied only a little over the
last year. However, most people living with HIV/AIDS haven't heard it.
A version of it appeared in the February 4 issue of the New England
Journal of Medicine ("The Immuno-pathogenesis of HIV Infection," pp
327-335) and another in the November 12 issue of the journal Science
(pp 1011-1018). I have attempted to summarize his essential arguments
here in language a bit more accessible than the original.
Like most researchers and observant lay people, PWA/HIVs included,
Fauci believes the evidence is overwhelming that HIV infection sets in
motion a long cascade of events resulting in profound damage to the
immune system and the diseases known as AIDS. To develop effective
treatment including ways to repair the damage to the immune system, it
is necessary to understand how the process of immune destruction
unfolds in the body, in all its phases and interactions with other body
systems. This total process is what scientists call
Many parts of the process are still not known and our knowledge in some
areas is being pushed by the competition of opposing hypotheses. Fauci
summarizes what's known about the process and where new treatment
approaches might logically work. This represents an advancement from
the days when we saw only slides of the HIV viral life cycle and
possible points where drugs might interfere with it. Fauci is saying
that stopping the virus's growth or infectivity is critical, but not
the only game in town; we also need to rebuild damaged immune systems.
INITIAL INFECTION AND WHAT FOLLOWS
A few weeks after someone is first infected with HIV, before the body's
immune system responds effectively, the virus replicates (reproduces
itself) explosively. Up to 70% of people have an acute flu-like illness
at this point. High levels of HIV can be found in the bloodstream. This
is probably when HIV gets "seeded" in various tissues of the body,
including the brain, lymph nodes, and other lymphoid tissues such as
cells in mucous membranes of the gastro-intestinal tract. T-cells and
some other white blood cells usually drop sharply in number during the
initial infection phase.
Within weeks to months, the body's immune system response to HIV is up
and running. The flu-like symptoms disappear, little or no HIV can be
found in the bloodstream for several years, and the T-cell count goes
back up (though usually not all the way to what it was before
The period that follows is known as "clinical latency," characterized
by the absence of symptoms. It was earlier believed that very little
HIV replication was happening. Most or all the virus was thought to be
lying dormant in infected cells.
We now know this isn't so. Quite a high level of the virus can be found
in the lymph nodes and in related tissue (50 to 60% of all the body's
lymph cells are found in the lining of the GI tract). There may be
other important body reservoirs for HIV that we don't yet know of. Some
of the HIV is trapped and immobilized in the lymph tissue and some is
waiting quietly after integrating itself into T-cell and macrophage
nuclei. But a substantial amount of HIV replication happens
persistently in the lymph nodes and tissues throughout the asymptomatic
The early seeding and continuous replication is a rationale for early
use of antiviral drugs. The problem is that we don't have any good
ones, ones that are safe to use for a long time and remain effective.
In Fauci's exact words, "the benefits of early intervention are usually
only temporary and do not result in significant long-term advantages
with regard to course of disease and death." However, once we have
safer and more effective antivirals, it makes sense to start using them
as early as possible.
CHRONIC ACTIVATION OF THE IMMUNE SYSTEM
In a healthy normal immune system, a foreign microbe or "antigen"
stimulates activation of various cells and production of chemicals
until the invader is adequately dealt with and cleared. Then the immune
system returns to a fairly quiet state until the next stimulus comes
along. This resting state between activation phases is essential for
the best possible function of the system. But in HIV infection, the
immune system stays activated all the time. This is probably one cause
of a gradual loss of immune function, even before the loss of immune
In addition, some scientists believe that either HIV or another microbe
(one target of the continuing search for a decisive "co-factor")
creates "superantigens," which can activate nearly all T-cells. If this
is true, it would contribute to the chronic overactivation.
Another compelling but as yet unproven theory is that autoimmune (the
immune system attacking the body itself) phenomena are generated early
on by HIV infection, which would also contribute to the persistent
Why is this chronic activation bad? Several reasons. For one thing, HIV
infects and integrates itself into activated cells more easily than
quiet ones. Also, activation of already infected T-cells stimulates the
generation and spread of more HIV within the body. Chronic activation
also stimulates the secretion of certain cytokines (immune system
messenger hormones) which in turn stimulate production of more HIV.
Furthermore, chronic activation causes competent immune cells to
gradually lose their ability to function. In a sense, the immune system
and its component parts begin to tire or burn out from the constant
Finally, chronic activation may stimulate a process called "apoptosis"
or programmed cell death. This is a way the body has of killing off
infected, impaired or otherwise undesirable immune system cells. The
hypothesis, as applied to HIV, is that many T-cells become exposed to
HIV (in the lymph nodes, for instance) without actually becoming
infected. However, they show evidence on their surface of having been
in contact and thus are sort of marked as "suspicious" and programmed
to commit suicide once they are stimulated and activated again.
What hope does all this have for therapy? One idea being tested is
intermittently giving immunosuppressive drugs to slow down or turn off
this hyperactivation. Cyclosporine A, an immunosuppressive drug used
to prevent rejection of organ transplants, is being investigated with
mixed but somewhat hopeful results so far.
Also, ways need to be found to interfere with this self-destructive
programming of uninfected T-cells (apoptosis). Finally, if these
superantigens are real and important, it's essential to kill them off
with effective antivirals or antibiotics.
ROLE OF CYTOKINES
These hormones are necessary to generate an initial response to a
foreign antigen and to maintaining the balance of the immune system.
There are many different cytokines (with names like Interleukin-2 or
IL-2, IL-6, interferon, tumor necrosis factor alpha or TNF alpha) and
they interact in a complex way. At certain stages of immune warfare or
maintenance, more of one is needed. Then when a particular job is done,
production of that one is turned way down or off and another one is
produced. In HIV infection, the normal cytokine rhythms and balances
are upset. Some of them cause more HIV replication. Others, like TNF
alpha, are associated with wasting.
Efforts to correct cytokine imbalances or block some of their negative
actions have been around for several years IL-2 and interferon alpha
for instance, or pentoxifylline (Trental) to try to block TNF alpha.
Though no dramatic therapeutic breakthroughs have occurred as yet,
efforts are picking up as scientists learn more about the cytokine
system. Quoting Fauci again, "given the clear-cut demonstration of the
role of cytokines in HIV pathogenesis and the apparent lack of serious
toxic side effects associated with pharmacologic attempts to
selectively block cytokine secretion or action, this approach should
be explored vigorously in clinical trials for the treatment of
HIV-infected individuals." (So Tony, in your role as director of the
major AIDS clinical trials systems, why aren't such vigorous clinical
trials up and running? I asked him this question recently and he said
he wrote this article from "the bully pulpit," hoping it would
stimulate researchers in the field to submit proposals along various
of these lines.)
PHYSICAL DESTRUCTION OF THE IMMUNE SYSTEM
The immune system has both floating (T-cells, macrophages, natural
killer cells, etc.) and stationary (lymph nodes and patches, bone
marrow, thymus gland) components. Both are vital. The mesh-like
structures in the lymph nodes, for instance (known scientifically as
follicular dendritic cell or FDC networks), act to trap HIV (and all
other invading microbes). This takes them out of circulation, allows
them to be killed and disposed of, and stimulates the B-cells of the
immune system to produce specific anti-HIV antibodies. In HIV infection
this works for a while and to an extent, but eventually these mesh
traps and associated B-cells start wearing out, growing weaker in
function and by late stage AIDS falling totally apart. This allows not
only HIV to run rampant, but removes a major bulwark against OIs and
other infectious microbes.
Similar loss of function and probably structure no doubt occur also in
the lymph tissue of the GI tract, the bone marrow, and the thymus
gland. (The bone marrow produces the precursors of T-cells which then
mature in the thymus, the immune system's "nursery.")
No one seems to be advancing any bright ideas about stopping this
structural decay except by getting better at stopping HIV replication
and spread itself.
However, there is exciting research (finally) into ways of
reconstituting damaged or destroyed components of the immune system.
(That this research is getting more and more attention is due largely
to the work of the late Jesse Dobson and Project Inform's Immune
Restoration Project.) The immune system has at least some capacity for
spontaneous regeneration. The immune systems of people given
immunosuppressive drugs for a variety of illnesses usually bounce back
when the drugs are stopped.
It is unclear if much spontaneous regeneration is possible in HIV
disease. The goal therefore is to figure out how to artificially
stimulate or assist the process. First, a lot more basic research needs
to be done, quickly and continuously. Second, tests and trials of the
partial ideas and substances need to be speeded up, carefully.
There are some encouraging small studies, such as the intermittent
infusion of IL-2 (5 days every 2 months) with resulting dramatic and
sustained (several months anyway) increases in T-cells for about half
the participants. IL-12 is another promising agent to stimulate
replacement of T-cells. IL-2 and IL-12 are also associated with the
TH-1 response of the immune system, referring to the first and more
effective stage of the immune response to HIV contrasted with the TH-2
response which comes later and is less effective. Giving the right form
and right doses of Il-2 and IL-12 might help the body revert from a
predominantly TH-2 to the more effective TH-1 response.
Various other potential pharmacologic and natural/herbal immune
enhancers have been and are being tried, with mixed or insufficient
results so far. This category includes everything from the Salk, gp160
and other therapeutic vaccines to polio and typhoid vaccines and DNCB.
After all this talk about the negative effects of hyperactivation of
the immune system, it may seem strange to be talking of ways to
stimulate or activate the immune system. However, under certain
circumstances (and particularly if accompanied by antiviral therapy)
intermittent stimulation of the immune system may help restore some
cellular components and functional competence to the immune system.
Another approach to restoration is to replace cells directly, through
bone marrow transplants or cloning and expanding cells outside the body
and then giving them back. None of these have yielded dramatic success
thus far, but their development is still in its infancy.
The thymus gland once again is key here, and has been studied least of
all. Though thymus transplants haven't shown much benefit, very few
have been attempted. Also, the body has some backup systems to the
thymus, probably mostly in the lymphoid tissue of the GI tract, that
need to be explored for their potential in a restoration program.
Gene therapy is another key area of treatment research, both in the
attempt to innoculate healthy immune cells against HIV infection and
to stimulate the production of new immune cells, such as by stimulating
the stem cells in the bone marrow.
The optimistic point of Fauci's review is to focus attention on many
aspects and phases of HIV infection and AIDS as possibly amenable to
therapy. A safe and effective antiviral is still lacking; when it
comes, as early and intensive (and perhaps comparatively brief)
intervention as possible seems logical. Meanwhile, other therapies
toward protection, support and restoration of the immune system need
to be pushed forward, but with an eye to the complexity of
immunopathogenesis and its stages.
On the other hand, the multifactorial and multiphase nature of AIDS
presents frustrating challenges to therapy. If you fix one problem you
may cause others. What may be good therapy at a specific early stage
of HIV infection may be a disaster later on.
We need to push for more basic research to solve the remaining puzzles
quickly. We in the community aren't as accustomed to learning the
intricate issues involved in basic research. Most of our experience has
been with clinical research, watching and pushing things near the end
of the drug pipeline. The depressing "no new therapies" news of 1993
reminds us that such a one-sided approach is just not good enough.