PMC

(A) CXCR4 inhibitors with an efficacy of at least 5% prevent CCR5 inhibitors from accelerating time to AIDS in the “competitive regime.” Relative to no treatment, the net time to AIDS onset is positive (i.e. AIDS onset is never accelerated) for any CCR5 inhibitor accuracy if CXCR4 inhibitors have an accuracy of at least 10%. (B) Similarly, HAART with an efficacy of at least 7% prevents CCR5 inhibitors from accelerating time to AIDS (i.e., having a negative net time) in the competitive regime. (C) Net time to AIDS with dual-treatment using CCR5 and CXCR4 inhibitors, each with 80% efficacy, across different values of k_M4 and k_M5 relative to no treatment. The net time to AIDS onset is never negative for dual treatment with CCR5 and CXCR4 inhibitors (i.e. AIDS onset never accelerated) when the inhibitors have strong efficacies. (D) The net effect of dual-treatment with CCR5 inhibitors and HAART, each at 80% efficacy, on the time to AIDS at different values of k_M4 and k_M5. The net time to AIDS onset is never negative for dual treatment with CCR5 inhibitors plus HAART (i.e. AIDS onset never accelerated) when the inhibitors and HAART have strong efficacies.

(A) A pedagogical model (schematic and numerical simulations) that is oversimplified to account for only a single target-cell population generates a competitively exclusive R5-to-X4 switch where R5 virus is cleared (i.e. goes extinct) following the switch, contrary to in vivo data . The model simulates a “phenotypic” switch occurring at a clinically representative time of 3–4 years post HIV-1 infection, and, notably, yields a concomitant decline in CD4⁺ T cell counts. The parameters used are λ = 33 cells/(µl•day), c = 23/day, p = 5750/day, δ = 0.7/day, k₄ = 5•10⁻⁴ µl/(virions•day), and k₅ = 10⁻⁴ µl/(virions•day). (B) A model restricting R5 and X4 to disparate target cell compartments can generate a clinically representative R5 to X4 switch over a large parameter regime and also exhibit coexistence of R5 and X4 post-switch. However, as shown in (C), such models cannot account for in vivo data showing that R5 inhibitors increase X4 levels . In (C), we apply a CCR5 blocker with a drug efficacy of 0.9, starting at t = 180 days. The model restricts R5 and X4 to independent target cell compartments, and, given the absence of viral competition, always generates strong suppression of X4 in response to CCR5 inhibition. Simulations in (B) and (C) are shown for a representative parameter regime: λ = 33 cells/(µl•day), c = 23/day, p = 2000/day, f = 0.8, δ = 0.5/day, k₄ = 0.0012 µl/(virions•day), and k₅ = 0.0034 µl/(virions•day).

(A) A schematic of Model 3, a competitive model with two target-cell populations. (B) The model exhibits a coreceptor switch at approximately 1000–1400 days post-infection in two types of parameter regimes: the “non-competitive regime” in (B, upper panel) and the “competitive regime” (B, lower panel). For the “non-competitive regime,” parameter values are: λ = 33 cells/(µl•day), c = 23/day, p = 2100/day, f = 0.8, δ = 0.5/day, k_N4 = 0.00108 µl/(virions•day), k_M4 = 4•10⁻⁵ µl/(virions•day), and k_M5 = 0.0068 µl/(virions•day), while in the “competitive regime” we change k_M4 to 5•10⁻⁴ µl/(virions•day) and k_N4 to 0.001 µl/(virions•day) (decreased in order to keep X4 in check). (C) The net effect of a CCR5 inhibitor with 80% efficacy on the time to AIDS across different k_M4 and k_M5 levels (i.e. different competitive and non-competitive regimes). AIDS onset is defined as the time at which CD4⁺ T cell counts fall below 200 cells/µl: negative values represent accelerated times to AIDS-onset relative to no treatment. R5 inhibitors clearly accelerate AIDS-onset for a large fraction of parameter space. (D) Time-dependency of X4 emergence as a function of CCR5 inhibitor efficacy (α-CCR5 efficacy) in the “competitive regime.” Increased CCR5 inhibitor efficacy accelerates X4 emergence and increases X4's viral set point.