Understanding the Slow Depletion of Memory CD4+ T Cells in HIV Infection

Abstract

BackgroundThe 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 FindingsUsing 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.ConclusionsA 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.

Modeling the three stages in HIV infection

“…However, [46] reported macrophage viral production that was too high to resolve by the techniques employed, indicating that viral production could be much higher than expected. As remarked in [12], CD4+T cell depletion in chronic HIV infection requires a slow process to drive the depletion of CD4+T cells. The model (14) is one possible mechanism for achieving such slow behaviour.…”

“…A number of previous works have examined some aspects of HIV infection, for example [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14]. These and other works present a basic relation between CD4+T cells, infected CD4+T cells and viral load [10], [13], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24].…”

Quantifying Thymic Export: Combining Models of Naive T Cell Proliferation and TCR Excision Circle Dynamics Gives an Explicit Measure of Thymic Output

“…Upon exit from cell cycle, it is rapidly degraded with a t 1/2 of ϳ1 h, independent of cell cycle position on exit from cycle (25). We can therefore use Ki67 to partition the naive CD4 ϩ population according to cell cycle status (at rest or cycling) and use a two-compartment model (33,34) to estimate the rate of addition of new cells to the naive population through peripheral division. This model is illustrated in Fig.…”

HIV induced suppression of host immunity: relevance to <i>Mycobacterium tuberculosis</i> infections

“…In untreated patients with progressive disease, the early HIV infection is characterized by high viral loads and decreasing CD4+ T cell counts, which lead to AIDS associated illness and OIs. It is also seen that the relentless but eventually rapid loss in CD4+ T cells are not only because of selective depletion by HIV [25,26], but also the decreased development of CD4+ T cells from precursor cells in thymus [27]. The early peak (acute phase) in the viral load is followed by the surge in antigen specific CD8+ T cells.…”