Modeling the Slow CD4+ T Cell Decline in HIV-Infected Individuals

<div><p>The progressive loss of CD4+ T cell population is the hallmark of HIV-1 infection but the mechanism underlying the slow T cell decline remains unclear. Some recent studies suggested that pyroptosis, a form of programmed cell death triggered during abortive HIV infection, is associated with the release of inflammatory cytokines, which can attract more CD4+ T cells to be infected. In this paper, we developed mathematical models to study whether this mechanism can explain the time scale of CD4+ T cell decline during HIV infection. Simulations of the models showed that cytokine induced T cell movement can explain the very slow decline of CD4+ T cells within untreated patients. The long-term CD4+ T cell dynamics predicted by the models were shown to be consistent with available data from patients in Rio de Janeiro, Brazil. Highly active antiretroviral therapy has the potential to restore the CD4+ T cell population but CD4+ response depends on the effectiveness of the therapy, when the therapy is initiated, and whether there are drug sanctuary sites. The model also showed that chronic inflammation induced by pyroptosis may facilitate persistence of the HIV latent reservoir by promoting homeostatic proliferation of memory CD4+ cells. These results improve our understanding of the long-term T cell dynamics in HIV-1 infection, and support that new treatment strategies, such as the use of caspase-1 inhibitors that inhibit pyroptosis, may maintain the CD4+ T cell population and reduce the latent reservoir size.</p></div

Schematic diagram of the one-compartment model.

<p>Inflammatory cytokines released during cell death by pyroptosis attract more CD4+ T cells (<i>T</i>) to be infected. The term <i>γ</i>_<i>i</i><i>C·kVT</i> represents cytokine enhanced viral infection due to increased CD4+ T cell availability.</p

Simulation of the one-compartment model with latently infected cells.

<p>(A) Population of latently infected T cells without cytokine enhanced homeostatic proliferation. (B) Population of latently infected T cells with cytokine enhanced homeostatic proliferation.</p

Fitting of the two-compartment model to the same patient data shown in Fig 9.

<p>Parameters values based on the best fits, 95% confidence intervals, and the AIC values of the fitting are listed in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004665#pcbi.1004665.t003" target="_blank">Table 3</a>.</p

CD4+ T cell dynamics predicted by the one-compartment model with different parameter values.

<p>(A) Sensitivity test on the infection rate <i>k</i>. The value of <i>k</i> increases from 1.44×10⁻⁸ (orange line) to 3.36 ×10⁻⁸ ml virion^-1 day^-1 (black line) with four equal increments. (B) Sensitivity test on the target cell generate rate <i>λ</i>. The value of <i>λ</i> increases from 6000 (orange line) to 14000 cell ml^-1day^-1 (black line) with four equal increments. (C) Sensitivity test on the viral production rate <i>p</i>_<i>v</i>. The value of <i>p</i>_<i>v</i> increases from 15000 (orange line) to 35000 virions cell^-1 day^-1 (black line) with four equal increments. (D) Sensitivity test on <i>γ</i>_<i>i</i>, the effect of cytokines on infection. The value of <i>γ</i>_<i>i</i> increases from 1.2×10⁻⁴ (orange line) to 2.8 ×10⁻⁴ ml molecule^-1 (black line) with four equal increments.</p

Fitting of the one-compartment model to patient data.

<p>Patient median was derived from two cohorts of studies in ref. [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004665#pcbi.1004665.ref025" target="_blank">25</a>] and MACS median was derived from the Multicenter AIDS Cohort Study in ref. [<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004665#pcbi.1004665.ref029" target="_blank">29</a>]. Parameters values based on the best fits, 95% confidence intervals, and the AIC values of the fitting are listed in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004665#pcbi.1004665.t002" target="_blank">Table 2</a>.</p

CD4+ T cell decline and viral load dynamics predicted by the one-compartment model.

<p>(A) CD4+ T cell decline consists of two major phases. A rapid and massive decline is caused by enormous viral infection during the early stage. It is followed by a progressive depletion phase, which is driven by pyroptosis enhanced viral infection. (B) Viral load dynamics generated by the one-compartment model with and without chronic inflammation.</p

Schematic diagram of the one-compartment model.

<p>Inflammatory cytokines released during cell death by pyroptosis attract more CD4+ T cells (<i>T</i>) to be infected. The term <i>γ</i>_<i>i</i><i>C·kVT</i> represents cytokine enhanced viral infection due to increased CD4+ T cell availability.</p

Influence of HAART on CD4+ T cell dynamics.

<p>(A) If treatment is very effective, then the CD4+ T cell population is predicted to be restored. (B) If drug efficacy is lower, then the later HAART is initiated the longer it takes for the T cell population to increase.</p

Schematic diagram of the two-compartment model.

<p>Parameters <i>σ</i>_<i>1</i> and <i>σ</i>_<i>2</i> represent the transportation rates of uninfected T cells between blood and lymph nodes. Cytokines (<i>C</i>) attract uninfected T cells (<i>T</i>_<i>1</i>) from blood into lymph nodes at an enhanced rate <i>γ</i>_<i>r</i><i>C</i>. Parameters <i>D</i>_<i>1</i> and <i>D</i>_<i>2</i> represent the transportation rates of virus between two compartments.</p