Wednesday, March 7, 2007

Is Mathematical Modeling of HIV Infection Good for Anything? by Rebecca Culshaw

About Rebecca Culshaw:

Rebecca Culshaw worked on mathematical models of HIV infection for almost ten years. She received her Ph.D. in mathematics (with a specialization in mathematical biology) from Dalhousie University in Canada in 2002 and is currently an assistant professor of mathematics at the University of Texas at Tyler. Her book, " Science Sold Out: Does HIV Really Cause AIDS?", is fast becoming a science best seller.

Dear Dr. Culshaw: Is Mathematical Modeling of HIV Infection Good for Anything?

Answer: Until very recently my answer to this question was something close to this.

It is an open secret in the mathematical biological community that there does not exist any satisfactory mathematical model of "HIV pathogenesis" and that "HIV modeling" is a dead-end field. The most well-known attempt to mathematically model HIV infection occurred in the Ho/Shaw papers of 1995. The influence of these papers had much more to do with the publicity department and editorial bias of Nature than the scientific merits of the work, as the manifest shortcomings of the papers were acknowledged (in private) by most mathematical biologists immediately following their publication, and then publicly in Nature Medicine in 1998 by Mario Roederer:

"There has been considerable debate about this simple hypothesis of Ho and Wei. Their 1995 Nature papers ignited a heated controversy that resulted in publication of several well-designed and informative studies, which raised serious doubts about this 'war'. In this issue of Nature Medicine, reports by Pakker et al. and Gorochov et al. provide the final nails in the coffin for Ho's and Wei's models of T cell dynamics, an illusion of faulty assumptions and poor measurement techniques."

Having said that, it is also true (and frequently pointed out) the abject failure to develop an adequate model of HIV infection does not mean that such a model does not exist, nor does it disprove that HIV causes AIDS. Yet after 20 years of intense effort resulting in failure, it does suggest that alternative models based on non-viral hypotheses of AIDS progression may merit study.

I wrote this very thing in a paper in the Journal of American Physicians and Surgeons in the Winter 2006 number ("Mathematical Modeling of AIDS Progression: Limitations, Expectations, and Future Directions") where I outlined a model based on the intracellular antioxidant glutathione and on the shift from Th1 to Th2 (subtypes of CD4+) cells observed in AIDS patients. (1)

One problem with all existing mathematical models of HIV infection is the simplistic treatment of CD4+ cells, which HIV allegedly "destroys" in some poorly-understand fashion -- variability in CD4+ measurements makes them almost useless in mathematical models, and treating all CD4+ cells as equal ignores the documented shift in AIDS progression among all CD4+ cells from Th1 (that "help" in cell-mediated immunity) to Th2 (that "help" in extracellular immunity and antibody production). (2-4)

The Th1-Th2 shift is strongly associated with an abundance of oxidized glutathione:

"Glutathione is found in both the reduced (GSH) and oxidized (GSSG) form. The ratio of GSH:GSSG has been shown to be important in regulating the Th1/Th2 balance. An excess of GSSG at the expense of GSH is generally considered a marker for severe oxidative stress. Also, GSH deficiency has been shown to inhibit NO [nitric oxide] synthesis, rendering the cellular immunity defense even more helpless. If the GSH:GSSG ratio declines, Th2 cells are preferentially manufactured, as Th0 cells are instructed to mature into Th2 cells. The net effect is a shift to Th2-dominance at the expense of Th1 cells, creating a reduced T-cell count in the bloodstream, and increasing susceptibility to opportunistic infections." (1) My suggestion does not require HIV as a variable, and offers a testable alternative to those produced by the "HIV infection" program.

Now that John Moore has been made aware of this paper, can we expect that he will write to the journal editor demanding a retraction?

Until very recently that would have been a sure bet. But if he was paying attention at the Fourteenth Conference on Retroviruses and Opportunistic Infections San Diego to what John Mellors was claiming, and what Mellors claimed finds its way from meeting abstracts to reputable journal, the odds-on becomes an odds-off. The journal will have no need to retract it as it will have become another of the tens of thousands of superfluous papers of HIV/AIDS research (but at least it will not be one of the deadly ones).

In something resembling a scientific farce, Mellors "defended" the conclusions of the "final nail" in the HIV/AIDS coffin of Rodriguez et al. by providing the following lead paragraph at the March 2 aids map news.

"The rate at which an untreated HIV-positive person's CD4 cell count is declining is a poor predictor of the risk of AIDS or death in individual patients the Fourteenth Conference on Retroviruses and Opportunistic Infections was told this week".

"This means that medium term CD4 decline – the quantity Rodriguez said was poorly predicted by viral load – is itself a useless predictor of progression to AIDS, because it is so immensely variable. In fact it is so difficult to calculate the gradient of a medium-term CD4 decline which may in fact feature short-term, abrupt increases and decreases such that the average statistical error in the calculation is 55 cells – almost equal to the average annual decline. In a quarter of the observations, the error of the slope is greater than the measurement of the slope itself," Mellors said.

Say that again? The rate of CD4 decline is not a predictor of AIDS? See why I quit HIV ?* - RC

1. Culshaw, Rebecca V., 2007. "Mathematical Modeling of AIDS Progression: Limitations, Expectations, and Future Directions", Journal of American Physicians and Surgeons, Volume 11 Number 4, Winter 2006, pp. 101-105.

2. Clerici M, Shearer G. "The Th1-Th2 hypothesis of HIV infection: new insights". Immunology Today, 1994; 15: 575-581

3. Mossman T. "Cytokine patterns during the progression to AIDS". Science, 1994; 265: 193-194.

4. Klein S, Dobmeyer J, Dobmeyer T, et al. "Demonstration of the Th1 to Th2 cytokine shift during the course of HIV-1 infection using cytoplasmic cytokine detection on single cell level by flow cytometry". AIDS, 1997; 11: 1111-1118.

Numbers art by Emma Holister ... for the numerically challenged ... but artistically willing ... trouble wiv numbers? ... get calculatin wiv football

artwork in portraits+sketches as well as the pier

1 comment:

Sepp said...

Great Article Emma,

good for finding and putting it up.

It is time we started to look at the biochemical details on Aids, which are very well known to the researchers, but somehow fail to find their way into the brains of policy makers and celebrities, who push ever more drugs on the sufferers of Aids in a mistaken belief that they have to "kill kill kill the virus"!

They only end up killing the patient instead.