Limited CD4+ T cell proliferation leads to preservation of CD4+ T cell counts in SIV-infected sooty mangabeys

Abstract

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections result in chronic virus replication and progressive depletion of CD4+ T cells, leading to immunodeficiency and death. In contrast, 'natural hosts' of SIV experience persistent infection with high virus replication but no severe CD4+ T cell depletion, and remain AIDS-free. One important difference between pathogenic and non-pathogenic infections is the level of activation and proliferation of CD4+ T cells. We analysed the relationship between CD4+ T cell number and proliferation in HIV, pathogenic SIV in macaques, and non-pathogenic SIV in sooty mangabeys (SMs) and mandrills. We found that CD4+ T cell proliferation was negatively correlated with CD4+ T cell number, suggesting that animals respond to the loss of CD4+ T cells by increasing the proliferation of remaining cells. However, the level of proliferation seen in pathogenic infections (SIV in rhesus macaques and HIV) was much greater than in non-pathogenic infections (SMs and mandrills). We then used a modelling approach to understand how the host proliferative response to CD4+ T cell depletion may impact the outcome of infection. This modelling demonstrates that the rapid proliferation of CD4+ T cells in humans and macaques associated with low CD4+ T cell levels can act to 'fuel the fire' of infection by providing more proliferating cells for infection. Natural host species, on the other hand, have limited proliferation of CD4+ T cells at low CD4+ T cell levels, which allows them to restrict the number of proliferating cells susceptible to infection.

Figure 1.

Relationship between CD4+ T cell number and proliferation level (by Ki67 expression): experimental data are shown from pathogenic infection of (a) rhesus macaques (RMs) or (b) HIV infection, as well as natural host infection of (c) sooty mangabeys (SMs) or (d) mandrills. The experimental data for RMs, humans and SMs are obtained from previously published studies (Paiardini et al. 2005, 2009b; Sumpter et al. 2007; Brenchley et al. 2008; Dunham et al. 2008; Engram et al. 2009) and for mandrills from unpublished results. All of the species except mandrills show a significant negative correlation between CD4+ T cell count and the proportion of cells Ki67+ (Spearman correlation). The relationship between total CD4+ T cell number and proliferation [r(T), solid line] is fitted with an exponential function (top). Parameters for best fit of exponential function to the data for each species, as well as the p-values, are shown in table 1. The baseline proliferation rate (D)—the average proliferation rate when CD4+ T cell counts are high (greater than or equal to 1000 cells per microlitre of blood for SM and RM, and greater than or equal to 500 cells per microlitre of blood for humans)—is very similar between species. However, the maximal proliferation (C + D) is higher in the more pathogenic hosts (RMs and humans) compared with SMs.

Figure 2.

Relationship between CD4+ T cell number and proliferation level (by Ki67 expression) after depletion of CD4+ T cells with antibody: (a) three uninfected RMs and (b) three uninfected SMs were treated with repeated infusion of the humanized anti-CD4 monoclonal antibody Cdr-OKT4A-huIgG1clone 12F11, and the fractions of CD3+,CD4+ T cells monitored over time by flow cytometry (as previously described; Klatt et al. 2008). Both Ab-depleted species show a significant negative correlation between CD4+ T cell count and the proportion of cells Ki67+ (Spearman correlation), even in the absence of virus. The relationship between total CD4+ T cell number and level of proliferation [r(T), solid line] is likewise fitted with an exponential function and the parameters, as well as the p-values, are shown in table 2.

Figure 3.

Higher proliferation leads to fewer remaining uninfected CD4+ T cells. (a) The relationship between the total number of uninfected CD4+ T cells and the proportion of these cells that are proliferating. Curves for pathogenic infection (peak proliferation 25%) are shown as dashed-dotted lines, and those for non-pathogenic infection (peak proliferation 5%) are shown as solid lines. (b) The relationship between the total number of uninfected CD4+ T cells and the number of proliferating CD4+ T cells (i.e. obtained from the curve in (a) by multiplying the proportion of proliferating cells by the number of uninfected cells). The equilibrium number of proliferating (i.e. susceptible) uninfected cells is 17 cells µl⁻¹ of blood. This level is reached when the total pool (proliferating and non-proliferating) of uninfected CD4+ T cells is 847 cells µl⁻¹ of blood for non-pathogenic infection, as shown by the solid line (with 2.0% proliferating), and 117 cells µl⁻¹ of blood for pathogenic infections, as shown by the dashed-dotted lines (with 14.8% proliferating). Equilibrium is shown as dashed line.

Figure 4.

Course of infection with different levels of proliferation: using identical infection parameters but varying the maximal proliferation, we found that a higher proliferation of CD4+ T cells at low CD4+ T cell counts (dashed-dotted line, pathogenic infection) led to fewer remaining uninfected CD4+ T cells and higher viral loads in chronic infection. By contrast, low proliferation (solid line, non-pathogenic infection) led to preservation of uninfected CD4+ T cells. The viral load in the non-pathogenic model was lower than the pathogenic, consistent with the experimentally observed difference in viral loads between RMs and SMs. Parameters: λ = 10 cells µl⁻¹ d⁻¹, ρ = 0.7 d⁻¹, k = 200 cells µl⁻¹, β = 3.3 × 10⁻⁶ ml per RNA copy per day, δ_I = 0.8 d⁻¹, p = 2.8 × 10⁵ RNA copies per cell per day, c = 20 d⁻¹.

Figure 5.

Functions used to describe the relationship between CD4+ T cell number and proliferation level: Using the data points for RMs as an example, the simple exponential (solid line), Hill function (dashed line) and piecewise linear (dashed-dotted line) functions were fitted to describe the relationship between CD4+ T cell number and proliferation level. However, the same divergent behaviour between pathogenic and non-pathogenic infection is observed regardless of the form of the functions used in the model.