PITTSBURGH, April 29, 1997 — A provocative new scenario of T cell activity in HIV infection challenges the biological reasoning and the mathematical approaches underlying two existing models of T cell decline in AIDS patients, according to an analysis presented by investigators from Tel Aviv University and the University of Pittsburgh in the May 1 issue of Nature Medicine.
One of the models challenged by the new theory has been particularly influential within scientific circles. Proposed by David Ho, M.D., of the Aaron Diamond AIDS Research Center in New York City, and colleagues and by others, the model has resulted in the introduction of new therapies for HIV disease.
The new analysis, which could suggest other new treatment avenues, stresses several novel aspects of HIV infection, including a distinct adaptive response of the body's immune system to the virus which renders many CD4 T lymphocytes, the most vulnerable target, variably resistant to infection with HIV. The analysis also suggests that cell types other than CD4 cells play an important role in sustaining the infection, not only as additional reservoirs of HIV but as part of the primary mechanism of HIV transmission among cells.
One model the new report challenges, called "failing homeostasis," by Dr. Ho, was proposed in 1995. At that time, when antiviral drugs were effectively used in patients to block continued infection of cells by HIV, the subsequent initial rise of CD4 cells in these patients was explained as a result of the rapid production of CD4 cells that existed before the treatment, and that now after treatment exceeded cell loss. Based on this interpretation, scientists estimated a rapid turnover rate of CD4 cells before treatment.
"Failing homeostasis" purports that HIV vigorously destroys CD4 cells from the outset of infection. Although the body can initially keep up and replace lost cells, maintaining a fairly stable steady state for several years, the highly accelerated CD4 cell turnover, according to this view, eventually exhausts the so-called homeostatic capacity of the immune system for maintaining its size and integrity. Inability to replace the lost cells quickly enough, during the time when patients have become infected with HIV but show no symptoms, is responsible for the falling CD4 cell counts and is also the direct cause of AIDS. The ongoing process has been likened to a sink in which CD4 cells eventually drain from the body faster than they can be replaced by the body's tap.
The reasoning for the "failing homeostasis" model is unsound, according to the authors of the Nature Medicine paper.
"In fact, the turnover of CD4 cells need not be considered out of the ordinary," noted Zvi Grossman, Ph.D., senior lecturer of physiology and pharmacology at Tel Aviv University and adjunct professor of biostatistics at the University of Pittsburgh. "Advances in understanding the immune system as a complex dynamic system, which manifests flexibility and adaptability in several ways, strongly suggest that the rise in CD4 cells after drug treatment for HIV infection is not the result of overproduction of these cells, a process already in motion, but rather an adaptive response to the decrease in virus. We and other investigators believe, for example, that CD4 cells are released into the bloodstream from other compartments. More importantly, the decline in CD4 cell counts which is the hallmark of HIV infection also reflects, in large part, an adaptive response rather than simply resulting from cell depletion. Bi-directional cross-talk' between immune cells and their local environment leads to continuous adjustment of cell migration and homeostasis."
Consideration of the possible physiological purpose of such adaptive response, from this perspective, points to possible innovations in treatment for HIV infection.
"Current models of HIV infection do not adequately take into account some basic aspects of T lymphocyte response to stimulation, which have been studied and conceptualized in recent years and which suggest that CD4 cells chronically exposed to HIV and to HIV- induced factors can become resistant to infection. Such resistance' is associated with a reduced ability of the cells to proliferate and circulate, which may partly explain the reduced levels of CD4 cells in the blood. Most researchers consider only conditions in which HIV exposure stimulates CD4 cell division and infection. We call the two concomitant processes differential activation.' Differential activation also points to novel ways of treating infection, perhaps by selectively promoting the generation of resistance in those CD4 cells that are more likely to become infected with HIV, thereby curtailing the active spread of disease," said Ronald Herberman, M.D., co-author, director of the University of Pittsburgh Cancer Institute and associate vice chancellor, Health Sciences, University of Pittsburgh.
Another relatively unexploited target for anti-viral therapy is the reservoir of macrophages and other non-CD4 cells located in lymph tissue throughout the body. Some of these cells are known to become infected with HIV although they contribute little to the virus load. Here again the authors of the Nature Medicine article question the mainstream view of the dynamics of infection.
"These other cells and other modes of infection may be as essential for sustaining the disease as the infection of CD4 T cells, because they live longer after being infected and because they are directly involved in cell-cell interactions whereby CD4 cells are activated and become susceptible to infection," Dr. Grossman said.
The article also challenges another current model of disease progression, "blind homeostasis," which claims that the body's control systems normally regulates only the sum of CD4 T cells and CD8 T cells (the other subset of T cells) at a fixed level, not each subset separately. Consequently, according to this hypothesis, selective killing of CD4 cells by HIV necessarily results in their progressive depletion, because the body is unable to distinguish and fully compensate for the loss. Under this model, the ratio between CD4 cells and CD8 cells would be expected to change over time even in healthy people. According to Drs. Grossman and Herberman, statistical analysis of T cell counts in a large number of people who were not infected with HIV has indicated a remarkable stability of the ratio between the two subsets over time that argues against the concept of blind homeostasis.