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Changes in CCR5+ cells and antigen-specific CD4+ T-cells during monotherapy with a CCR5 antagonist SCH532706 compared with combination therapy

Background

CCR5 regulation appears important in Th1 cell recruitment to sites of inflammation/infection. HIV- and CMV-specific CD4+ T-cells are CCR5+. Maraviroc, a CCR5-receptor blocker licensed for HIV treatment, is associated with an increased incidence of upper respiratory tract and Herpes infections.

Methods

We investigated changes in CCR5+CD4+ and CD8+ T-cell subsets, plasmacytoid dendritic cells (PDC) and antigen-specific CD4+ cells in HIV (R5-tropic)-infected subjects given SCH532706 with ritonavir (/r) for 10 days, followed by a 15-day "washout" (day 11–25), and commencing combination antiretroviral therapy (cART) on day 25. Median decline in plasma HIV-RNA (VL) after 10 days of SCH532706/r vs. cART was -1.5 and -1.75 log10 copies/mL (p = 0.7, respectively. CD4+ cells specific for Mycobacteria tuberculosis and avium (M.TB, MAI), cytomegalovirus (CMV), Herpes simplex (HSV), HIV Gag, CCR5+ cell subsets, and PDC were measured at days 1, 3, 10 (phase 1); 20, 25 (phase 2); and 25, 28, 35 on cART (phase 3). Changes were analysed using the Mann-Whitney test. Changes in CCR5+ T-cell subsets were assessed by area-under-the-curve comparisons.

Summary of results

Ten males, with median 242 CD4+ (range 93–551), 783 CD8+ (range 353–1115) T-cells/μL, VL 4.5 log10 copies/mL (range 3.8–5.7), were enrolled. At baseline, 20% of CD4+ and 50% of CD8+ T-cells were CCR5+; CD4+ cells specific for M.TB, MAI, CMV, HSV, HIV Gag were 0.45%, 5.7%, 5.0%, 2.3% and 1.75%, respectively. Median changes in CD4+ T-cells during phases 1, 2, 3 were +16, -26, +28 cells/μL, respectively (1 vs. 3: p = 0.7); CD8+ T-cell changes were +91, -142, -71, respectively (1 vs. 3: p = 0.7). Relative to baseline, changes in CCR5+CD4+ T-cells for phases 1, 2, 3 were +22%, -24% and +24%, respectively (1 vs.3 p = 0.7). In contrast, CCR5+CD8+ T-cell changes were +33%, -13% and -10%, respectively (significant for phases 1 vs. 2 and 1 vs. 3; both p = 0.01). PDC increased during phase 1 compared to phases 2 (p = 0.02) and 3 (p = 0.04). Equivalent declines in percentages of M.TB-, CMV-, HSV-, and Gag-specific CD4+ cells occurred during phases 1 and 3. MAI-specific CD4+ cells declined on cART vs. SCH532706/r (p = 0.037).

Conclusion

CD4+ T-cell increases were modest on SCH532706/r and cART. CCR5+CD8+ T-cells and PDC increased substantially during receipt of the CCR5-antagonist, but not cART, suggesting alterations in trafficking due to CCR5 blockade. Declines in CMV, HSV and HIV Gag responses were equivalent during receipt of SCH523706/r and subsequent cART.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Pett, S., Zaunders, J., Bailey, M. et al. Changes in CCR5+ cells and antigen-specific CD4+ T-cells during monotherapy with a CCR5 antagonist SCH532706 compared with combination therapy. JIAS 11, P297 (2008). https://doi.org/10.1186/1758-2652-11-S1-P297

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  • DOI: https://doi.org/10.1186/1758-2652-11-S1-P297

Keywords

  • Herpes Simplex
  • Ritonavir
  • Plasmacytoid Dendritic Cell
  • Maraviroc
  • CCR5 Antagonist