A new study, published today in the online peer-reviewed journal PLoS Medicine, refutes a longstanding theory of how HIV slowly depletes the body's capacity to fight infection. Using a simple mathematical model, Andrew Yates, PhD, of Emory University and his colleagues, show that a "runaway" cycle of CD4 cell activation and infection cannot explain the slow rate of CD4 cell decline during chronic HIV infection.
HIV causes disease by inactivating the body's immune responses. Most severely affected are the CD4 cells – the white blood cells that recognize infection and orchestrate the activities of other components of the immune system to control it. Following rapid loss and recovery during the first few weeks of HIV infection, there is a much more gradual drop in the CD4 cell count – in the absence of antiretroviral treatment – often over a period of ten years or longer.
For over a decade, some researchers have been inclined to use a "tap and drain" analogy when describing the slow CD4 cell loss. According to this model, CD4 cells (like water in a sink) are constantly being eliminated by HIV (the drain), while the body is constantly replacing them with new ones (the tap). Over time, the tap cannot keep up with the drain. As a result, the CD4 counts begin to drop, ultimately allowing the cancers and infections that are the hallmark signs of AIDS.
But what actually leads to this imbalance? One increasingly popular explanation for CD4 cell loss is the "runaway" hypothesis, in which CD4 cells infected with HIV produce more virus particles, which activates more CD4 cells that in turn become infected, leading to an ongoing cycle of CD4 cell activation, infection, HIV production, and cell destruction.
Does the "runaway" hypothesis explain why CD4 cell counts fall so slowly in HIV infection? Using a mathematical model, Dr. Yates' group concluded that, if the "runaway" hypothesis were correct, then CD4 cells would fall much more rapidly – to low levels over a few months, not over several years. They therefore conclude that the "runaway" hypothesis cannot explain the slow pace of CD4 cell depletion in HIV infection.
According to one of the paper's authors, Jaroslav Stark, PhD, of Imperial College London, "Scientists have never had a full understanding of the processes by which [CD4] cells are depleted in HIV, and therefore they've been unable to fully explain why HIV destroys the body's supply of these cells at such a slow rate. 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."
Because of the model's simplicity, the authors conclude, the study is convincing in its rejection of the runaway hypothesis. However, a more detailed analysis is necessary to determine what, exactly, the the slow process is.
One possibility raised by Dr. Yates and his colleagues is the slow adaptation of the virus itself over the course of infection. Specifically identifying this process, they argue, will provide a key insight into the nature of HIV disease and indicate potential new approaches to therapy.
Source:
Yates A, Stark J, Klein N, et al. Understanding the slow depletion of memory CD4+ T cells in HIV infection. PLoS Med 4(5):e177. Accessed May 22, 2007 at: PLoS Medicine.
