Predicted viral load decay for the quad and RAL-combination treatments using the best fit of the SRI model (Eq (1) when <i>δ</i>₂ = <i>δ</i>_<i>M</i>2) to the data.

<p>The estimated population parameters for each treatment group where used to plot the viral load decline under the effect of RAL+RTI (red) and quad therapy (blue). The dotted blue and red lines show the analytical approximation for the second phase of decay for quad therapy and RAL-combination therapy, respectively (see equation S.14 in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006478#ppat.1006478.s001" target="_blank">S1 Text</a>). The shadowed section highlights phase 1b for RAL-combination therapy. The viral load at the start of phase 2 in patients under RAL-based therapy is reduced with respect to the corresponding level in RAL-free therapy by a factor of . We fixed the values of the following parameters (see text for details): <i>V</i>_<i>I</i>(0)/<i>V</i>(0) = 0.98, <i>δ</i>_<i>M</i>1 = 0.02 day^-1, <i>k</i> = 2.6 day^-1 and <i>c</i> = 23 day^-1 based on previous studies [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006478#ppat.1006478.ref014" target="_blank">14</a>,<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006478#ppat.1006478.ref016" target="_blank">16</a>,<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006478#ppat.1006478.ref039" target="_blank">39</a>]. In addition, for RAL combination we used <i>η</i> = 0.95, <i>ε</i> = 0 and <i>ω</i> = 0.94, and for the quad therapy <i>η</i> = <i>ε</i> = 0.95 and <i>ω</i> = 0 [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006478#ppat.1006478.ref014" target="_blank">14</a>]. The estimated best-fit population parameters are (estimated standard deviation in parenthesis): <i>δ</i>₁ = 0.23 (0.04) day^-1, <i>k</i>₁ = 0.017 (0.01) day^-1, <i>δ</i>₂ = 0.85 (0.07) day^-1 and <i>V</i>(0) = 4.8 (0.07).</p

Schematics of the models.

<p>(A) The standard model with pre- and post-integration phases of infection. We follow two types of target cells that after infection will be short-lived, , or long-lived, . Target cells, , are infected by infectious virus, <i>V_i</i>, at rate . The infection can be blocked by the activity of RTIs with effectiveness <i>η</i>. These infected cells, <i>I</i>₁, are lost at rate <i>δ</i>₁, or can undergo provirus integration at rate <i>k</i> and become productively infected cells <i>I</i>₂. InSTIs block integration with efficacy <i>ω</i>. Cells with integrated provirus, <i>I</i>₂, are lost at rate <i>δ</i>₂. Virions are produced by these cells at rate <i>p</i> per cell and are cleared from the circulation at rate <i>c</i> per virion. Protease inhibitors block the production of infectious virus <i>V</i>_<i>Ii</i>, and lead to production of non-infectious virus <i>V</i>_<i>Ini</i>, with efficacy <i>ε</i>. The subscripts <i>I</i> and <i>M</i> are used to distinguish virions produced by short-lived and long-lived infected cells, respectively. The dynamics of long-lived cells are similar, but possibly with different rates as indicated. (B) The slow and rapid integration (SRI) model. The SRI model proposes that both short-lived cells with fast integration (<i>I</i>₁) and long-lived cells with slow integration (<i>M</i>₁) generate productively infected cells that die quickly (<i>I</i>₂) (i.e. <i>δ</i>₂ = <i>δ</i>_{<b><i>M</i>2</b>}<b>)</b>.</p

Viral dynamics after the initiation of treatment with or without RAL.

<p>(A) Blue and pink lines show the viral load relative to baseline for study participants in the QUAD treatment and RAL-combination therapy, respectively. Black lines represent the median values for each group. In the last phase, between about day 15 and day 30, the viral load in the RAL-combination participants is ~1-log lower (Δ~90% reduction) than the viral load in the quad-therapy group participants. (B) The median viral load profiles for each group present two phases of decay (1a and 2), but in addition the RAL-combination therapy includes an intermediate phase, 1b.</p

Comparison of the viral load decay rates during treatment with or without RAL.

<p>Rows represent each phase of decay and columns the estimates for each treatment using two methodologies: a heuristic multi-exponential model (two columns on the left) and the SRI model in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006478#ppat.1006478.g002" target="_blank">Fig 2B</a> and Eq (<b><a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006478#ppat.1006478.e008" target="_blank">1</a></b>) (two columns on the right). The estimation of the rate for phase 1b is only applicable in the case of treatment with RAL. All values are in units of day^-1. For the SRI model, we also indicate the parameter combination defining the decay rate of each phase.</p

Representative individual fits for the three datasets.

<p>Blue, red and green circles represent HIV RNA measurements for the quad-based-, RAL-combination- and RAL-mono therapy, respectively. Solid black lines represent best fits from the SRI model using the mixed-effects approach. Parameter estimates for each individual are presented in Table E in <a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1006478#ppat.1006478.s001" target="_blank">S1 Text</a>.</p

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02 juillet 19201920/07/02 (A49).Appartient à l’ensemble documentaire : PoitouCh

Patient characteristics.

<p>HIV-1-infected patients are from the A5248 cohort and controls were taken from a cohort of uninfected persons with at least two cardiovascular disease risk factors.</p><p>Patient characteristics.</p

Gating strategy for flow cytometry and comparison between fresh and cryopreserved monocyte surface marker expression.

<p>(A) Shown are isotype control dot plots and CD14 and CD16 expression in freshly obtained and cryopreserved PBMC from the same healthy volunteer and the expression of CX3CR1 on each monocyte subset in the cryopreserved sample. Monocyte subsets were gated using the isotype staining as a guide, as seen in the farthest left panel. Traditional monocytes are in purple, inflammatory monocytes are in pink, patrolling monocytes are in green. Gates are drawn based on negative isotype staining using Rat IgG2b, in the case of CX3CR1. (B) Summary surface marker expression, both proportion and MFI, in fresh and cryopreserved PBMCs on total monocytes of healthy control subjects, with medians, are shown. Each shape (triangle, square, diamond, and circle) represents an individual healthy control subject. (C) Summary surface marker expression, both proportion and MFI, in fresh and cryopreserved PBMCs on total monocytes of virologically suppressed HIV-infected subjects, with medians, are shown. Each shape (triangle, square, diamond, and circle) represents an individual HIV-infected subject.</p

Alterations in surface marker density on total monocytes and monocyte subsets of HIV-1-infected patients before and after initiation of ART.

<p>Baseline MFI values are italicized if significantly greater than among uninfected controls and boldedif significantly lower by Mann Whitney U tests. Comparisons were made between week 12 and baseline (0–12), week 24 and baseline (0–24), and week 48 and baseline (0–48) using both Wilcoxon signed rank test and the generalized estimating equation. Significant increases (p<0.05) are italicized and significant decreases are bolded. Robust Z score for the GEE plot are included to aid in the understanding of the direction of the change; negative Z score indicates decreased values after ART initiation and positive Z scores indicate increased values after ART initiation</p><p>Alterations in surface marker density on total monocytes and monocyte subsets of HIV-1-infected patients before and after initiation of ART.</p

Alterations in frequencies of surface marker expression on total monocytes and monocyte subsets of HIV-1-infected patients before and after initiation of ART.

<p>Baseline proportions are italicized if significantly greater than among uninfected controls and bolded if significantly lower by Mann Whitney U tests. Comparisons were made between week 12 and baseline (0–12), week 24 and baseline (0–24), and week 48 and baseline (0–48) using both Wilcoxon signed rank test and the generalized estimating equation. Significant increases (p<0.05) are italicized and significant decreases are bolded. Robust Z score for the GEE plot are included to aid in the understanding of the direction of the change; negative Z score indicates decreased values after ART initiation and positive Z scores indicate increased values after ART initiation.</p><p>Alterations in frequencies of surface marker expression on total monocytes and monocyte subsets of HIV-1-infected patients before and after initiation of ART.</p