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Being Alive
Multifactorial Nature of HIV Disease: Implications for Therapy (or: "Dr. Fauci's Standard Talk, Summarized in English")
Walt Senterfitt
January 5, 1994
Being Alive 1994 Jan 5: 3

INTRODUCTION 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 illness.

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 "immuno-pathogenesis." 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 infection).

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 phase.

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 system cells.

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 hyperactivation.

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 stress.

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.

IMMUNE RECONSTITUTION 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.

CONCLUSION 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.

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