Intensification of antiretroviral therapy with a CCR5 antagonist in patients with chronic HIV-1 infection: effect on T cells latently infected

Carolina Gutiérrez, Laura Díaz, Alejandro Vallejo, Beatriz Hernández-Novoa, María Abad, Nadia Madrid, Viktor Dahl, Rafael Rubio, Ana M Moreno, Fernando Dronda, José Luis Casado, Enrique Navas, María Jesús Pérez-Elías, Javier Zamora, Sarah Palmer, Eduardo Muñoz, María Ángeles Muñoz-Fernández, Santiago Moreno, Carolina Gutiérrez, Laura Díaz, Alejandro Vallejo, Beatriz Hernández-Novoa, María Abad, Nadia Madrid, Viktor Dahl, Rafael Rubio, Ana M Moreno, Fernando Dronda, José Luis Casado, Enrique Navas, María Jesús Pérez-Elías, Javier Zamora, Sarah Palmer, Eduardo Muñoz, María Ángeles Muñoz-Fernández, Santiago Moreno

Abstract

Objective: The primary objective was to assess the effect of MVC intensification on latently infected CD4(+) T cells in chronically HIV-1-infected patients receiving antiretroviral therapy.

Methods: We performed an open-label pilot phase II clinical trial involving chronically HIV-1-infected patients receiving stable antiretroviral therapy whose regimen was intensified with 48 weeks of maraviroc therapy. We analyzed the latent reservoir, the residual viremia and episomal 2LTR DNA to examine the relationship between these measures and the HIV-1 latent reservoir, immune activation, lymphocyte subsets (including effector and central memory T cells), and markers associated with bacterial translocation.

Results: Overall a non significant reduction in the size of the latent reservoir was found (p = 0.068). A mean reduction of 1.82 IUPM was observed in 4 patients with detectable latent reservoir at baseline after 48 weeks of intensification. No effect on plasma residual viremia was observed. Unexpectedly, all the patients had detectable 2LTR DNA circles at week 24, while none of them showed those circles at the end of the study. No changes were detected in CD4(+) or CD8(+) counts, although a significant decrease was found in the proportion of HLA-DR(+)/CD38(+) CD4(+) and CD8(+) T-cells. LPS and sCD14 levels increased.

Conclusions: Intensification with MVC was associated with a trend to a decrease in the size of the latent HIV-1 reservoir in memory T cells. No impact on residual viremia was detected. Additional studies with larger samples are needed to confirm the results.

Trial registration: ClinicalTrials.gov NCT00795444.

Conflict of interest statement

Competing Interests: Pfizer Inc. provided the drug. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1. Consort Flow Diagram.
Figure 1. Consort Flow Diagram.
Figure 2. Effect of MVC intensification on…
Figure 2. Effect of MVC intensification on HIV-1 latently infected memory CD4+ T cells.
(a) Patients who had a latent reservoir below the limit of detection at baseline, and remained undetectable after 48 weeks of intensification. (b) Patients with quantifiable latent reservoir at baseline, and decreased after 48 weeks of intensification, (c) patients with quantifiable latent reservoir at baseline but discontinuated the study after w12. Square symbols: detection limit of 0.12 IUPM. Diamond symbols: detection limit of 0.023 IUPM. Open symbols: under the limit of detection.
Figure 3. Immune activation during MVC intensification.
Figure 3. Immune activation during MVC intensification.
CD4+ and CD8+ T cell activation of the patients during the follow up is shown. A group of HIV-1 negative individuals are also shown.
Figure 4. CD8
Figure 4. CD8
+T cell subpopulations after MVC intensification. The proportion of naïve, central memory (TCM), effector memory (TEM), and effector memory RA+ (TemRA) cells is shown.
Figure 5. Proportion of CD8
Figure 5. Proportion of CD8
+T cells expressing β7 receptor. A) naïve T cells, B) memory T cells, and C) activated T cells.
Figure 6. Bacterial translocation.
Figure 6. Bacterial translocation.
Levels of sCD14 and LPS during the follow up are shown. The levels of a group of HIV-1 positive naïve for ART are also included.

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