Book Review
New Concepts in AIDS Pathogenesis
N Engl J Med 1994; 330:1026April 7, 1994
- Article
New Concepts in AIDS Pathogenesis
Edited by Luc Montagnier and Marie-Lise Gougeon. 323 pp., illustrated. New York, Marcel Dekker, 1993. $99.75. ISBN: 0-8247-9127-4One of the penalties of working in a field too long is that more and more of what seems important happened over a decade ago. That was when patterns of AIDS transmission were discerned, human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) were discovered, and zidovudine, arguably our most effective antiretroviral drug, was identified. Yet the puzzle of how CD4+ T lymphocytes die in patients with AIDS -- a problem of fundamental importance to the biologic features of HIV and critical to the development of novel therapeutics -- evades our grasp. Basic knowledge of T-cell homeostasis is inchoate and simplistic; most investigators believe that AIDS would not occur if one could block virus-mediated destruction of the thymic, bone marrow, and lymph-node microenvironments, regardless of the control of HIV replication.
This book, a collection of 19 papers based on a symposium held in June 1992 at Annecy Lake, France, summarizes several divergent and occasionally conflicting hypotheses about fundamental mechanisms of AIDS pathogenesis. Well organized and edited, with minimal overlap among sections, it is largely comprehensible to an audience conversant with the rudiments of virology and immunology, but it is quite out of date.
In the chapter “Cytokines and HIV Expression,” by Fauci and colleagues, the ability of interleukin-2 and other growth factors to up-regulate HIV replication in vitro is duly noted. But a noteworthy new finding of this group is that interleukin-2, given intermittently in high doses, augments CD4+ T-cell counts in patients with HIV disease, with only transient and clinically irrelevant elevations in viral burden.
Imberti and associates review their work on the T-cell-receptor repertoire in AIDS. They present data on the depletion of certain T-cell-receptor subgroups of CD4+ T cells and postulate that HIV proteins may induce cross-reactive antibodies that interact with particular T-cell-receptor Vβ chains. A good idea, but inadequate methods. One month after this symposium, our group showed that HIV can interact directly with the T-cell receptor, like a superantigen, and that there is a lack of selective depletion of T-cell-receptor phenotypes, a conclusion subsequently supported by numerous other studies.
A key chapter, “Immunological and Virological Mechanisms of CD4+ T Cell Depletion,” is concise and scholarly but is concerned primarily with viral phenotype and quantitative studies of peripheral blood. This approach ignores the very rapid alterations in primary lymphoid tissues shortly after an acute HIV-1 infection -- changes that appear to be quite distinct from those in the blood. And information on HIV-modulated differentiation of CD4+ T-cell subpopulations -- the type 1 and type 2 helper T cells, thought to be important in both therapeutic and vaccine strategies -- is omitted.
The best discussions relate to HIV and apoptosis, the “falling apart” of T lymphocytes attendant on the activation of genes for cell death, or the failure to induce mechanisms that block apoptosis. Drs. Gougeon and Montagnier excel at describing this phenomenon. Over the years Professor Montagnier has taken a remarkably esemplastic approach to AIDS. His gift for shaping ostensibly disparate observations into a unified whole is apparent in all the chapters to which he contributes.
Despite the omissions I have noted, AIDS researchers can only benefit from a study of the chapters by Folks, Goudsmit, Ameisen, and others included here for some clue to the next 10 years of advances in HIV research. This book also shows why a Manhattan Project for AIDS would be of dubious value. The very factors that promote success in war -- cohesion, conformity, and obedience -- can only dictate failure in new thought.
Jeffrey Laurence, M.D.
Cornell University Medical College, New York, NY 10021
