Anti-proliferative therapy for HIV cure: a compound interest approach

Abstract

In the era of antiretroviral therapy (ART), HIV-1 infection is no longer tantamount to early death. Yet the benefits of treatment are available only to those who can access, afford, and tolerate taking daily pills. True cure is challenged by HIV latency, the ability of chromosomally integrated virus to persist within memory CD4+ T cells in a non-replicative state and activate when ART is discontinued. Using a mathematical model of HIV dynamics, we demonstrate that treatment strategies offering modest but continual enhancement of reservoir clearance rates result in faster cure than abrupt, one-time reductions in reservoir size. We frame this concept in terms of compounding interest: small changes in interest rate drastically improve returns over time. On ART, latent cell proliferation rates are orders of magnitude larger than activation and new infection rates. Contingent on subtypes of cells that may make up the reservoir and their respective proliferation rates, our model predicts that coupling clinically available, anti-proliferative therapies with ART could result in functional cure within 2-10 years rather than several decades on ART alone.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1

Schematics of models for HIV dynamics on and off ART. The top panel shows all possible transitions in the model (equation (1)). The bottom shaded panel shows the available transitions for the decoupled dynamic equations when ART suppresses the virus. Model parameters are given in Table 1. HIV virus V infects susceptible cells S at rate β reduced by ART of efficacy ε to βε. The probability of latency given infection is τ. The rate of activation from latently infected cells (L) to actively infected cells (A) is ξ. Cellular proliferation and death are determined by rates α and δ for each compartment. The mechanisms of action of anti-proliferative and latency reversal therapies are to decrease αL and increase ξ, respectively.

Figure 2

Simulated comparisons of latent reservoir eradication strategies on standard antiretroviral (ART) treatment. Treatment thresholds (discussed in Methods) are shown as solid black lines both in the plots and color bar, which is consistent between panels. (a) One-time therapeutic reductions of the latent pool (L0). (b) Continuous therapeutic increases in the clearance rate (θL). Relatively small decreases in the clearance rate θL produce markedly faster times to cure than much larger decreases in the initial reservoir size. (c–e) Latency reversal agent (LRA) and anti-proliferative (AP) therapies are given continuously for durations of weeks with potencies given in fold increase in activation rate (εLRA) and fold decrease in proliferation rate (εAP), respectively. The color bar is consistent between panels, and thresholds of cure are shown as solid black lines both on plots and on the color bar. (c) Latency reversing agent therapy (LRA) administered alone requires years and potencies above 100 to achieve the cure thresholds. (d) Anti-proliferative therapies (AP) administered alone lead to cure thresholds in 1–2 years provided potency is greater than 2–3. (e) LRA and AP therapies are administered concurrently, and the reduction in the latent pool is measured at 70 weeks. Because the proliferation rate is naturally greater than the activation rate, increasing the AP potency has a much stronger effect than increasing the LRA potency.

Figure 3

Simulated comparisons of anti-proliferative therapies on standard antiretroviral therapy (ART) assuming variable reservoir composition. Proliferation and death rates in Table 1. The potency of the therapy is εAP = 10 (i.e., each cell type i has proliferation rate equal to αi/10 with i∈[em,cm,n]). Plausible initial compositions of the reservoir (Li(0)) are taken from experimental measurements, , . It is assumed that the HIV activation rate ξ is equivalent across all reservoir subsets. (a–c) Plots of times to therapeutic landmarks on long-term ART and anti-proliferative therapy with heterogeneous reservoir compositions consisting of effector memory (Tem), central memory (Tcm), and naïve plus stem cell-like memory (Tn + Tscm) CD4+ T cells. Tem and Tn + Tscm percentages are shown with the remaining cells representing Tcm. Times to one-year remission and functional cure are extremely sensitive to percentage of Tn + Tscm but not percentage of Tem. (d,e) Continuous 10-fold therapeutic decreases in all proliferation rates (αi) result in Hill 1-yr in (d) 3.5 years assuming Tn + Tscm = 1% and (e) 6 years assuming Tn + Tscm = 10%. The reservoir is predicted to become Tn + Tscm dominant within 2 years under both assumptions, providing an indicator to gauge the success of anti-proliferative therapy in potential experiments.

Figure 4

Global sensitivity analysis. We use the ranges of parameters from Supplementary Table S4. (a) 1,000 simulations drawn from Latin Hypercube sample parameter sets where R0ART<1 are shown to demonstrate the variability of latent pool dynamics with respect to all combinations of parameter ranges. (b) The time until each cure threshold, Pinkevych 1-yr (P1) and Hill cure (Hc), are calculated as the time when the latent reservoir contains fewer than 20,000 and 200 cells respectively. In some cases cures are achieved within months. In others, cure requires many years. (c) Pearson correlation coefficients indicate the correlations between each variable and time to cure. L0 is the initial number of latent cells. Ln(0)/L0 is the initial fraction of naïve cells in the latent pool. τ is the probability of latency given infection. R0ART is the basic reproductive number on ART. εART is the percent decrease in viral infectivity in the presence of ART. θL is the decay rate of latent cells. εAP is the fold reduction in proliferation rate.

Figure 5

Waning anti-proliferative potency over-time modulates cure. Latent reservoir dynamics on combined ART and anti-proliferative therapy simulated for waning potency of anti-proliferative therapy over time. The latent reservoir size is shown with horizontal black lines corresponding to the cure threshholds used throughout the paper. Cure thresholds are achieved within 10 years if potency decreases by less than 5% per month considering 1% naïve T cells (Ln(0)/L0 = 0.01) and initial anti-proliferative potency εAP = 5.

Figure 6

MMF pharmacodynamics. Pure mycophenolic acid (MPA) was added to CEM cells at varying concentrations and proliferation of CEM cells was measured to determine a dose-response curve and Hill slope. CD4+ T cells from stored peripheral blood mononuclear cell samples from 10 participants (4 HIV-infected, 6 HIV-uninfected) were stimulated to proliferate. CD4+ T cells from 3 HIV-negative subjects were sorted into effector memory (EM), central memory (CM), and naïve subsets. Pure MPA was added to these cells at varying concentrations in order to determine IC50s for MPA. (a) Dose-response curve with percentages of CEM cells proliferating at varying doses of MPA. The Hill slope is −3.7. (b) 4 samples from HIV-positive participants and 6 samples from HIV-negative participants had similar IC50s. (c) IC50s were similar among CD4+ effector memory (EM), central memory (CM), and naïve T cell subsets.