A new paper in PLoS Medicine by Andrew Yates and colleagues makes a valiant attempt to mathematically model the impact of HIV infection on CD4 T cell homeostasis in humans. The authors carefully review recent published data on the factors that are involved in the maintenance of CD4 T cells, including variables relating to the major CD4 subsets (naïve and memory) and potential states (activated versus resting) in order to try and ascertain how HIV infection and HIV-related immune activation might lead to the gradual decline in peripheral blood memory CD4 T cell counts that occurs during chronic HIV infection. The resultant data shows that, based on the authors’ assumptions, HIV infection should lead to a much more rapid decline of memory CD4 T cell numbers than in fact occurs.
To look more closely at the assumptions that underlie the mathematical model, the authors posit that memory CD4 T cells turn over (in a process known as homeostatic self renewal) about once every 60 days, and that this turnover occurs more often (once ever 30 days) under conditions of memory CD4 T cell depletion. These assumptions are in broad agreement with the published literature. More speculatively - and controversially - the authors assume that this turnover renders the cells susceptible to HIV infection, despite the fact central memory CD4 T cells are not thought to express CCR5 during this process. The estimated lifespan of HIV infected CD4 T cells in the model is 0.5 days, and this is derived from a David Ho paper published in Science in 1996. The authors also construct a more complex model that takes into account antigen driven CD4 T cell activation as well as homeostatic turnover, which predicts that memory CD4 T cell depletion should occur even faster than predicted by the simpler model.
There are some other potentially controversial aspects of the paper: not least, the authors dispense with recent data describing the rapid depletion of mucosal CD4 T cells by focusing on the subsequent chronic phase of infection. The paper states that the goal was to keep the model as simple as possible and the results are based on changes to total body memory CD4 T cell numbers and do not appear to take into account redistribution of memory CD4 T cells from the blood into the lymphoid tissue (this phenomenon is known to account for a significant amount of memory CD4 T cell loss from the blood in HIV infection). Also, as far back as 1994 the late Janis Giorgi and colleagues reported that people with AIDS are not preferentially depleted of phenotypically defined memory CD4 T cells as the peripheral blood CD4 T cell count declines, a finding echoed by a comprehensive analysis of total body CD4 T cell counts in SIV-infected macaques which found that total CD4 T cell numbers were slightly increased during the asymptomatic phase of the infection and did not decline significantly until the late stage of disease. However, it may be that these phenomenon - like the slow decline of peripheral blood memory CD4 T cells - would, based on the model, also not be explained solely by elevated memory CD4 T cell activation and turnover. The authors also list some additional caveats and considerations in the discussion section of the paper, and suggest that viral adaptation to the immune system environment may play a role in memory CD4 T cell depletion.
In an interesting supplemental analysis, the authors adapt the model to include the possibility that every time a CD4 T cell is activated, there is a small probability that the CD4 T cell will become exhausted and dysfunctional. The analysis demonstrates that, under these circumstances, the model would in fact predict the slow accumulation of dysfunctional memory CD4 T cells and the progressive lowering of CD4 T cell counts over a period of years that occurs in people with HIV infection. Given that there is abundant evidence that dysfunctional memory CD4 T cells do accumulate in people with HIV, this analysis may offer some important insights into the role of T cell exhaustion in HIV pathogenesis, although the authors note that additional data is needed to fully explore this possibility.
One final odd note about this study is that the Imperial College Press Office produced an accompanying press release which has the potential to be extremely misleading. The release is entitled “HIV's effect on white blood cells questioned by new research” which some media outlets have changed to “Study Refutes Theory on HIV's Effect on White Blood Cells” because of the press release’s subtitle which says “Scientists have refuted a longstanding theory of how HIV slowly depletes the body's capacity to fight infection, in new research published today.” The only problem – and it’s quite a large problem – is that it is entirely unclear which theory (if any) is being refuted. According to the press release, “one popular theory has been the ‘runaway’ hypothesis” - but there is no such hypothesis! The phrase “runaway” is coined by the study authors in the PLoS Medicine paper, without citation, and the phrase appears nowhere in the literature on HIV pathogenesis. I emailed the Imperial College press office just in case I’d missed a citation somewhere, but they have not yet responded.
UPDATE: I received an email from Jaroslav Stark acknowledging that there is indeed no "runaway" hypothesis.
"The term "runaway" was indeed our own since we needed a simple term with which to refer to such a class of models within the manuscript. As I am sure you are aware, a number of authors, including Grossman, Hellerstein, Hazenberg, Feinberg & Silvestri have proposed such explanations. I agree that these have
never been clearly unified into a single theory in the literature. I do not think that we suggest anywhere that this is the case, but rather we identify the common denominator in all of these various theories and then show that this always leads to a much quicker decline in CD4+ numbers than is observed in practice."
UPDATE 2: The BBC website seems to have developed an odd habit of publishing stories many weeks or months after the fact; on Saturday June 23 they unfortunately decided to add to the misinformation surrounding this modeling exercise with a story headlined "HIV infection theory challenged." Stark is quoted as saying "our new interdisciplinary research has thrown serious doubt on one popular theory of how HIV affects these cells, and means that further studies are required to understand the mechanism behind HIV's distinctive slow process of cellular destruction." Researchers focusing on the role of immune activation in HIV pathogenesis will doubtless be surprised to learn that not only have they all agreed on one theory, it has apparently also become popular!
UPDATE 3: In a surfeit of annoyance at the inaccuracy of the media coverage of this paper, I now realize - with the help of a thoughtful and informative email from Dr. Stark - that the first few iterations of this post were overly (and inaccurately) critical of the paper itself. Although the lifespan of infected memory CD4 T cells assumed in the model is taken from a David Ho paper that posits cytopathicity as the driving force causing cell death, altering the lifespan of infected cells such that it is equivalent to uninfected cells may not necessarily change the model significantly (although this analysis has not yet been performed). It is perhaps asking a lot to expect researchers engaged in the complex and arcane art of modeling CD4 T cell homeostasis to be savvy about the way a media story can be abused (as regrettably, this story has been by the cult-like group known as AIDS denialists).
UPDATE 4: The global circulation of the extremely misleading press release associated with this study continues: Popular HIV Theory "Wrong," We've Got it Wrong About HIV, Theory of How HIV Attacks is Wrong. After trying to be generous toward the authors of the paper, it is hard to escape the conclusion that - whether it was naivete or something worse - they have made a huge and unwelcome contribution to the public misunderstanding of HIV science.
PLoS Med 4(5): e177
Andrew Yates1,2*, Jaroslav Stark3,4, Nigel Klein5, Rustom Antia1, Robin Callard2,5
1 Department of Biology, Emory University, Atlanta, Georgia, United States of America, 2 Centre for Mathematics and Physics in the Life Sciences and Experimental Biology, University College London, London, United Kingdom, 3 Department of Mathematics, Imperial College, London, United Kingdom, 4 Centre for Integrative Systems Biology at Imperial College, Imperial College London, United Kingdom, 5 Immunobiology Unit, Institute of Child Health, London, United Kingdom
The asymptomatic phase of HIV infection is characterised by a slow decline of peripheral blood CD4+ T cells. Why this decline is slow is not understood. One potential explanation is that the low average rate of homeostatic proliferation or immune activation dictates the pace of a “runaway” decline of memory CD4+ T cells, in which activation drives infection, higher viral loads, more recruitment of cells into an activated state, and further infection events. We explore this hypothesis using mathematical models.
Methods and Findings
Using simple mathematical models of the dynamics of T cell homeostasis and proliferation, we find that this mechanism fails to explain the time scale of CD4+ memory T cell loss. Instead it predicts the rapid attainment of a stable set point, so other mechanisms must be invoked to explain the slow decline in CD4+ cells.
A runaway cycle in which elevated CD4+ T cell activation and proliferation drive HIV production and vice versa cannot explain the pace of depletion during chronic HIV infection. We summarize some alternative mechanisms by which the CD4+ memory T cell homeostatic set point might slowly diminish. While none are mutually exclusive, the phenomenon of viral rebound, in which interruption of antiretroviral therapy causes a rapid return to pretreatment viral load and T cell counts, supports the model of virus adaptation as a major force driving depletion.
PLoS Med 4(5): e193
Time Scales of CD4+ T Cell Depletion in HIV Infection (free access)
Rob J. De Boer