Pursuing HIV Alone As A Therapeutic Target Has Been A Faulty AIDS Research Strategy

In the debate over HIV as the sole "cause" of AIDS, I have come to the conclusion that, in addition to HIV, there are many other influences playing upon the immune system of patients. I believe that it is essential that we avoid being doctrinaire on the basis of evidence that is still incomplete. My views on these matters have been tempered by the fact that, as shown by my colleagues Robert F. Garry at Tulane University, Marlys H. Witte at the University of Arizona, and others (R.F. Garry, M.H. Witte, et al., Journal of the American Medical Association, 260:2085-7, 1988), HIV infection had occurred in the United States as early as 1968. In all likelihood, others were also infected at that time, but the infection did not result in epidemic pathogenicity in the U.S. until the early 1980s. Why was this so? We really do not know the answer to that question, but an important possibility is that the sexual revolution with the concomitant increase in sexually transmitted disease, the heightened use of illicit drugs, the availability of disposable plastic syringes and needles, and other factors that increasingly came into play in the 1970s provided conditions that were favorable for increased transmission of what is now called HIV and development of its pathogenicity. While a great deal is known about the fine genetic structure of HIV, relatively little is known about how this virus causes the severe immune dysfunction that is associated with HIV infection. A key question that remains open is whether HIV alone is sufficient to cause disease in any given patient at a given time, or whether the pathogenicity of HIV is dependent on, or contributes to, other factors that are independently capable of perturbing the immune system. Pursuing HIV alone as a therapeutic target has, in my mind, been a faulty strategy, since it assumes that HIV itself is responsible for all of the manifestations of HIV disease and ignores the probable contributions to the disease process of a variety of other cofactors that impact adversely on the immune system. Cofactors that have been implicated by Michigan State University's Robert Root-Bernstein and others include the presence of other sexually transmitted diseases; the use of illicit drugs; the role of foreign white blood cells, which can be transmitted intravenously or between sexual partners; and poor nutrition. To the extent that these cofactors and others contribute to the state of immunologic imbalance in this disease, they cannot be addressed or corrected by an antiviral drug. Reduction in levels of HIV or its components, in a given patient, will not necessarily correlate with slowing of disease progression and/or correction of immune dysfunction if cofactors are indeed integral to the disease process. I am convinced, on the basis of my experience in the field, that control of HIV disease will not occur until the underlying state of immune dysfunction becomes a primary focus of treatment. We also need a much better understanding of the influence of these cofactors on CD4+ cells (critical regulatory cells of the immune system, sometimes referred to as T-helper cells). In my view, there has been an excessive emphasis paid to CD4+ cell numbers as opposed to CD4+ cell function. The latter is the really critical issue determining a patient's course, and yet the number of CD4+ cells has become the relevant immune surrogate. Of course, CD4+ cells decline in number over the course of HIV disease, but every CD4+ cell is not equal to every other CD4+ cell. Much more needs to be learned about the behavior of CD4+ cell subsets over the course of the disease and what effect(s) changes in the function of particular CD4+ subsets have in patients over time. The same can be said in respect to CD8+ cells, since particular CD8+ subsets have been implicated in cytotoxicity against HIV. In my view, there has been an excessive emphasis on attacking the virus itself, rather than focusing, as well, on the fact that HIV disease, from a clinical point of view, is a complex problem of disordered immune function. That is what is responsible for the morbidity and mortality of the disease, including the multiple clinical indicia that are now taken to define AIDS. What is needed is the aggressive development of therapeutic agents capable of affecting cell-mediated immune function, and further testing of these agents for their ability to alter the course of HIV disease. A. Arthur Gottlieb is professor and chairman of the department of microbiology and immunology and a professor of medicine at Tulane University School of Medicine.

Pursuing HIV Alone As A Therapeutic Target Has Been A Faulty AIDS Research Strategy

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