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Being Alive
What's New In Basic Research?
Walt Senterfitt
October 5, 1992
Being Alive 1992 Oct 5: 7

The biggest question I take each year to the international AIDS conferences is: Why don't we have a cure yet and what's being done to change that? My biggest frustration each year is that I bring this same question home with me, not satisfactorily answered. This year, while still frustrated and angry, I came home convinced that at least the questions being asked by the basic scientists were more comprehensive and pertinent. Minds were more open to new explanations of problems that have been roadblocks, and the building blocks of solutions are being accumulated, in some areas at a gratifying pace and in other areas too slowly.

A big part of the answer to my first question is, of course, political, financial, and organizational. There is no cure because there have not been enough resources devoted to finding one and the research effort has furthermore been disorganized, inefficient, and underled. Not surprisingly, the Conference dealt little with this aspect of finding a cure.

Part of the delay is the complexity of the targets, HIV and this multifaceted syndrome of AIDS, complicated by severe limitations on what medicine knew at the epidemic's outset about the immune system and how to fight viral infections. Blame for this part of "no cure yet" is hard to assign, but the solution is straightforward: devote the quantity and sophistication of resources commensurate with the complexity and elusiveness of the target.

Another reason for no cure yet, though, is scientific and intellectual. Most scientists and physician specialists resist and/or find it very hard to break through the mental blinders imposed by the structure and obligations of their own disciplines and the conventional scientific wisdom or paradigms of their time.

STANDARD MODEL OF AIDS For example, most HIV/AIDS research has been informed by what might be called the "standard viral disease" model proposed by research virologists and clinical infectious disease specialists. This model (by model I mean a schematic description of a theory, a kind of intellectual cartoon picture, for a complex body process that no one understands for sure and which is very difficult to observe directly) holds that HIV replicates inside T-helper cells, causes the cell to lyse (burst) and then the offspring circulate to infect and kill more T-cells. This theory is the basis for antiviral therapies like AZT and ddI.

Aside from the fact that effective antiretroviral drugs have proven very difficult to develop, this model's major weakness has been that so few T-cells are infected (with the most sophisticated techniques of finding and counting the virus, less than 1% in asymptomatic HIV+ people to somewhat less than 5% in PWAs with very late stage disease). In addition, this model has difficulty explaining defects in immune functioning that occur very early on in the process.

The problems with this model have led various people to challenge the assumption that "HIV causes AIDS." Many of these critiques have been from the scientific (Peter Duisberg) and community (NY Native) fringes. Many of the scientific establishment responses have been defensive, seeming to lock them further into viewing AIDS through defective lenses.

[My own view of this specific question is that the empirical evidence indicates HIV to be a NECESSARY cause of almost every case of what we know as AIDS, but not a SUFFICIENT cause in all cases about 10% of some HIV+ cohorts show no immune abnormality after 13+ years of infection and another 10% with only moderate immune dysfunction and probably not the SOLE cause in many if not most cases.] FROM FRINGE TO CENTER STAGE For the best scientists at this Conference, the problems with this theory and its offshoots have moved from the fringes to center stage. Research was presented which tried to better explain the mechanisms of pathogenesis.

Some of this work remained within an essentially viral disease framework. For instance, many studies presented evidence for the significance of mutations of the virus into more lethal strains. For individuals, most or all of these strains have evolved from the one that originally infected them, but the process is still poorly understood. Five major varieties of HIV1 have been found worldwide (up from the two thought to predominate as of last year's Conference). At least one, found most commonly in Asia, is significantly more infectious than the others. It is not yet known whether this strain also leads more rapidly to severe disease.

Mutations appear to cause the much-discussed syncytium-inducing (SI) strains of virus which are associated with worse disease courses than are non-syncytium-inducing strains (NSI). Thus far, however, these syncytia (clumping or fusing of virus particles) have not been found in the bodies of people with HIV/AIDS, but only in laboratory studies. The development of SI strains in a person may be a marker for some other event that occurs, rather than the direct cause of the poor prognosis. Once again more research needed, and more correlation with the life of the virus in our bodies and not just in the laboratory, but viral mutation may be indeed important.

Studies presented reflected a lot more experience than last year in techniques of measuring "viral load," or the amount of virus in the circulating blood at any time. Though still a tool of research labs rather than widespread in the community, it can be done reliably in enough places to offer a new way of rapidly estimating effectiveness of antiviral drugs and the correlation of viral changes with symptoms and changes in condition.

HIV NOT SO QUIET EARLY ON The virologists also reported more investigations into what happens to HIV in the body during the whole course of infection, not just during active disease. Dr. Tony Fauci, for example, presented slides of lymph nodes of people at various stages of the disease. Among other things, his slides represented technical advances that enable scientists to detect and show HIV particles on such slides and to tell which ones are actively replicating.

Fauci's slides (including those of Mark Harrington see his report in the August-September issue) showed actively replicating virus in the lymph nodes of people who are entirely without symptoms and have more than 500 T-cells, in other words the "clinically latent" stage of the disease. The HIV infection is certainly not latent or quiet here "behind the scenes," even though no immune dysfunction has yet been detected.

This surprised many conferees and its significance is still unknown. Perhaps the body, while failing to eliminate the virus, is still managing to contain it mostly within the lymph nodes. The normal structure of the lymph nodes was still apparently intact and all major components of the immune system were present.

The slides of people with 300-500 T-cells looked markedly different from those with more than 500 T-cells. Some of the structures had died or disappeared (specifically, many of the follicular dendritic cells and B cell germinal centers). How and why this deterioration in the lymph nodes occurred, no one knows. The lymph nodes from people with late stage AIDS were virtually unrecognizable devastated terrain someone likened to Sarajevo.

Lest this seem unrelievedly grim, these and similar experiments could be seen on the one hand to add evidence and urgency for the earliest possible treatment of HIV infection, when T-cell counts are still high, in fact, as high as possible or as soon as HIV infection is known. The problem with this conclusion, of course, is that the drugs we can use to treat it are all toxic and only partially effective. (Get on the stick, you guys, and find a non-toxic antiviral!) IMMUNOLOGY TO THE FORE Another implication of Fauci's experiments, joining several other intellectual rivulets at the Conference, is to open new appreciation of the complexity (and perhaps contradictory nature) of the immune system's early and medium-term response to HIV infection. In Fauci's slides, this is starkly posed by the picture of many T-helper cells trapped in the mesh-like structure of the lymph nodes (created by the follicular dendritic cells), which should be a precursor to their being immobilized and killed. Yet some of these T-cells are actively producing new HIV.

This may be because the trapping of the T-cells stimulates other immune cells (B cells) to produce more anti-HIV antibodies (a good thing). In turn the stimulated B cells manufacture lots of B cell growth factors (cytokines, which are hormone-like proteins produced by immune system cells). Unfortunately, these same growth hormones also stimulate production of HIV. So, the body's attempt to control HIV may actually result in producing more HIV.

If I haven't lost you, this is just one example of why it is urgent to understand much, much more about what happens in the immune system at all stages of infection. We need to learn how to influence the immune system to PERMANENTLY control, if not eliminate, HIV). In other words, an adequate model of AIDS must be immunologic, as well as virologic.

Many current controversies about HIV are born of our still-inadequate knowledge. For instance, should we focus on stimulating or boosting the immune system's response early on? Or is this exactly wrong because it will lead either to more HIV production a la Fauci's slides or to a "chronic fatigue" and ultimate collapse of the immune system from constantly fighting a low grade infection? In some autoimmune diseases one gets better results by doing what seems paradoxical, to kill off some of the immune system cells and slow down the immune system a while so as to allow rest and a stronger resurgence later.

Seem hopeless? Not necessarily, just a lot of work that needs to be done, at the lab bench and with well-conceived treatment experiments in knowledgeable volunteers. I think it is much better that the controversies be aired, thinking thus refined, and new experiments conceived. This happened more in Amsterdam than before.

CONTROVERSY PUSHES PROGRESS For instance, there was one standing-room-only forum where five competing theories of pathogenesis (specifically, theories about how the stocks of T-helper cells in one's body are depleted) were presented by their proponents, with supporting evidence. The concepts presented included autoimmunity, programmed cell death (or apoptosis), and superantigens. This should have been a longer session with more time for debate, and should have been a model for many other sessions where significant controversy exists. Nevertheless, it was a hopeful development in a world where controversy is so often suppressed, drowned in ego, or at best highly stylized.

Dr. Jonas Salk put forth a theory which generated another controversy concerning the proper approach to a preventative vaccine. Usually vaccines are intended to stimulate antibodies against an invading organism, i.e. to stimulate a humoral immune response. Salk noted, however, that animal studies of HIV-related viruses, experiences with some other viral diseases in humans, and studies of health care workers exposed to HIV all indicate that humoral (antibody) immunity to HIV would not be successful in preventing HIV infection.

Rather, he proposed vaccine developers should explore using much smaller amounts of active ingredients to evoke a cellular immune response, i.e. one based on the direct "killer cells" of the immune system, rather than antibodies. His theories, if corroborated, may have implications for the current crop of therapeutic vaccines as well (those intended to boost the immune system of people already HIV+).

Immune system components, particularly the cytokines which provide the communication and regulation for much immune functioning, are being discovered almost weekly. Many of these discoveries were presented. Some have near-term implications for development of treatments, such as posing the task of finding inhibitors for IL-6 (one of the growth factors which stimulate B cell growth but also HIV) and IL-10 (one factor involved in shutting down the cellular immune response and stimulating the humoral one). I think, though, it will be lucky if one of these immediate offshoots works miracles by itself.

The complexity of the immune response means that almost every cell and growth factor in the immune system plays constructive roles at some points and destructive ones at others. Only with much fuller knowledge might we have some confidence in knowing when to "upregulate" and when to "downregulate." The good news is that this knowledge is finally coming along quite rapidly.

As we've said here in a number of ways, immunologic research is also vital to those with already well-established HIV infection or even advanced disease, because it includes seeking methods of immune system restoration. Alas, there was little enough of that described at the Conference, because the work is scarce and recent. However, there was a great deal of interest in the few gene therapy and CD8-expansion presentations.

The questions posed by Mark Harrington in his talk reported here last month remain, largely unanswered by this Conference. They were, however, on the agenda and were taken up by the most aggressive and foresighted investigators.

What can we in the PWA/HIV community do to speed the process? Accepting the challenge of becoming involved in shaping, monitoring, and bird dogging basic as well as clinical research. Continuing to fight for expanded funding of AIDS and all other medical research funds (DOUBLE the NIH budget next year! DAMN the depression!). And demanding scientific and logistic coordination of the research effort ("so that the kingdom is not lost for want of a nail").

This package is often summarized as a demand for a "Manhattan Project" to conquer AIDS, recalling the massive effort that led to the unprecedented rapid development of a "successful" atomic bomb by the US government in World War II. I agree with the effort and urgency required but strongly suggest we change our icon of reference. The Manhattan Project was, after all, an exercise in mass murder whereas we seek a mass rescue and lifesaving operation of world historic proportions. Any suggestions for a new name for our campaign? 

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