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The Hypothesis that Wasn't

Posted by plosmedicine on 31 Mar 2009 at 00:11 GMT

Author: Richard Jefferys
Position: Coordinator, Michael Palm Basic Science, Vaccine and Prevention Project
Institution: Treatment Action Group
Submitted Date: July 27, 2007
Published Date: July 30, 2007
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

It is extremely regrettable that this paper has so greatly misled people about HIV pathogenesis research. The problems begin with the PLoS Medicine summary:

"one popular explanation for CD4+ cell loss is the 'runaway' hypothesis."

The "runaway hypothesis" is not popular, because it does not exist. There is not a single citation in the scientific literature that refers to a runaway hypothesis, until this paper by Yates and colleagues. I would have hoped that the editors of PLoS Medicine would have been aware of this fact, but apparently not. The ignorance of the PLoS Medicine editors on this subject unfortunately directly contributed to the completely erroneous media headlines associated with this paper: "We've Got it Wrong About HIV" "HIV Infection Theory Challenged" etc., etc. (these media articles are also currently being featured on the front page of the PLoS Medicine website).

What Yates and colleagues attempt to do in their paper is create a hypothesis from various published studies and commentaries regarding the role of immune activation in HIV pathogenesis. But, as Yates et al correctly state in their paper: "Chronic immune activation (IA) is frequently cited as an erosive force, although it remains more of a strong association than a detailed mechanism."

The reason that there is as yet no "detailed mechanism" is the complexity of CD4 T cell homeostasis and remaining uncertainties regarding which immune system cells are getting activated, and why, and what the consequences of persistent activation are for the memory T cell pool (not just CD4 T cells, but CD8 T cells also).

For the purposes of their modeling exercise, Yates and colleagues made assumptions regarding the mechanisms by which immune activation might cause CD4 T cell decline, called this the "runaway hypothesis" and then showed that it would lead to a faster memory CD4 T cell decline than is seen in reality. As such, they haven't refuted any theory, or proven anyone wrong. To my knowledge, no one else has previously argued that all the assumptions used by Yates and colleagues are correct.

I do not mean to suggest that the modeling exercise was not useful or interesting, within the constraints of the assumptions that inform it. But to portray the paper as it has been by PLoS Medicine, the Imperial College press office and the media is a travesty, and a vast and unwelcome contribution to the public misunderstanding of HIV research.

No competing interests declared.