AIDSWEEKLY Plus, Monday, 16 December 1996
Daniel J. DeNoon, Senior Editor

Yes, say Northwestern University researcher Steven M. Wolinsky and colleagues, who published a paper to this effect in the journal Science (1996;272(5261):537-542, see AIDS Weekly Plus, May 20, 1996).

No way, say University of Oxford researcher Martin A. Nowak and colleagues, who developed the theory in 1990 (AIDS, 1990;4:1095) and defended it against Wolinsky et al. in a recent issue of Science ("HIV-1 Evolution and Disease Progression," Science, 1996;274(5289):1008-11).

In a nutshell, the theory of Nowak et al. holds that the immune system of an infected individual exerts evolutionary pressure on the virus to expand the diversity of its antigens in order to escape immune surveillance. Eventually, this antigenic diversity exceeds a certain threshold - different for every individual - beyond which the immune system becomes exhausted and AIDS results.

In their earlier paper, Wolinsky et al. pointed to data obtained from extensive study of six individuals - two with rapid CD4 decline, two with slow CD4 decline, and two with stable CD4 counts.

Contrary to what they felt the Nowak et al. theory predicts, they found that it was the stable patients who had the greatest viral diversity. The patients with rapid progression of HIV disease maintained relatively homogeneous virus populations throughout their infection, even when their CD4 counts dropped precipitously.

Nowak et al. responded to the Wolinsky paper by stressing that the threshold condition they propose can vary widely among individuals.

"The key result [of our theory] is a dynamic threshold condition that specifies whether or not the HIV population in a given patient is controlled by immune responses," Nowak et al. wrote. "In particular, weak immune responders should have a low antigenic diversity threshold and can therefore progress to disease rapidly and without significant antigenic variation."

In patients with a very weak anti-HIV immune response, Nowak et al. argued, "even a single [viral] strain can overcome the threshold."

But Wolinsky et al. remain unconvinced. In their rebuttal to Nowak et al., they said that the "plasticity" of the mathematical model from which the antigenic diversity theory is derived makes the theory untestable.

"A diversity threshold of 'one strain' cannot be considered a threshold because a lower value of diversity is not possible," they wrote. "Furthermore, a stochastic simulation of these 'weak immune responders' models a viral burden that continues to escalate exponentially. This is not biologically plausible."

The corresponding author for the Nowak et al. article is Martin A. Nowak, Department of Zoology, University of Oxford, South Parks Road, OX1 3PS Oxford, United Kingdom.

The corresponding author for the Wolinsky et al. response is Steven M. Wolinsky, Northwestern University Medical School, 303 East Chicago, Tarry Building, 3-735, Chicago, Illinois 60611-3008. Email: smw006@anima.nums.nwu.edu.

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