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Clinical Trial
. 2012 Oct 24;18(1):1240-8.
doi: 10.2119/molmed.2012.00206.

CCR5 antagonism impacts vaccination response and immune profile in HIV-1 infection

Samantha J Westrop  1 , Graeme Moyle, Akil Jackson, Mark Nelson, Sundhiya Mandalia, Nesrina Imami
Affiliations
Clinical Trial

CCR5 antagonism impacts vaccination response and immune profile in HIV-1 infection

Samantha J Westrop et al. Mol Med. .

Abstract

Maraviroc (MVC) is the first licensed antiretroviral therapeutic agent to target a host cell surface molecule, and successful HIV-1 entry blockade by this C-C chemokine receptor type 5 (CCR5)-antagonist potentiates immunomodulation. We hypothesized that MVC intensification impacts immunization responses, T-cell phenotype, function and delayed type hypersensitivity (DTH) in HIV-1(+) subjects. A 24-wk, double-blinded, placebo-controlled study of the addition of MVC to suppressive antiretroviral therapy in HIV-1(+) persons was performed. Subjects received DTH tests, intramuscular tetanus, meningococcal and oral cholera immunizations. Antibody titers, T-cell function and phenotype were assessed. Of 157 patients referred, 47 were randomized 1:1; MVC:placebo. MVC enhanced meningococcal neo-immunization, blunted cholera response and expedited lymphoproliferation to tetanus boost, without affecting recall humoral response. Anti-HIV-1 group-specific antigen (Gag) and tetanus toxoid (TTox) function improved significantly, HIV-1-associated CD8 T-cell skewing normalized, and the percentage of late-stage and major histocompatibility complex (MHC) class II expressing CD4 T-cells increased. Activated CD4(+) CD38(+) human leukocyte antigen (HLA)-DR(+) T-cells declined, and costimulation shifted to coinhibition. DTH was unchanged. Maraviroc intensification, through antagonism of the cell surface molecule CCR5, favorably influences immune profiles of HIV-1(+) patients, supporting its immunomodulatory use in HIV-1 infection and potentially in other immunologically relevant settings.

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Figures

Figure 1
Figure 1
Study design. Patients enrolled in the study attended for a total of eight clinical visits. Assessments and interventions performed at each visit are detailed. Concomitant medication was continued and adverse events monitored throughout. Blinded 1:1 randomization of participants into MVC and placebo arms occurred at baseline, with drug packs lasting 24 wks. Detailed immunology and HIV clinical care was performed at screen, baseline, wks 4, 12, 16 and 24. Ab, antibody.
Figure 2
Figure 2
Referral, screening, randomization and completion of treatment. Thirty percent of 157 patients referred were randomized into the two treatment arms at baseline. Twenty-four participants were assigned to receive placebo and 23 assigned to receive 150 mg MVC b.i.d.. Seventeen participants in the placebo arm completed the study to wk 24, compared with 20 in the MVC arm. DNA, did not attend; DO, dropout; ITT, intent to treat; LTFU, lost to follow up.
Figure 3
Figure 3
Humoral and T-cell-mediated responses showing significant changes from baseline over the 24-wk study period, in the context of MVC intensification and immunization. Changes from baseline in: (A) anti-tetanus antibody titers; (B) anti-MenC antibody titers; and (C) anti-CTB antibody titers. Change from baseline in IFN-γ production to stimulation with: (D) HIV-1 Gag20; and (E) TTox. (F) Change from baseline in proliferative response to stimulation with TTox. Mean changes from baseline estimated by mixed model analysis are plotted with bars above and below representing 95% confidence interval. Significance from baseline is shown by error bars that do not bisect the x axis, and is marked with *. Relevant immunizations are indicated by vertical dashed lines. All immunizations were administered at the time point indicated, after blood was drawn for immunological assessments. Ab, antibody.
Figure 4
Figure 4
Changes from baseline in phenotypic markers expressed on CD8 and CD4 T-cells over the 24-wk study period. Changes from baseline in percentage of CD8 T-cells expressing (A) CD28+CD27+ (early), (B) CD28−CD27+ (intermediate), (C) CD28−CD27− (late) and (D) CD27+. (E) Changes from baseline in mean fluorescence intensity (MFI) of CTLA−4 expressed on CD8 T-cells. Changes from baseline in the percentage of CD4 T-cells expressing (F) CD28−CD27− (late) and (G) CD28+, and MFI of (H) CD28 and (I) CTLA-4 expressed on CD4+ T-cells. Changes from baseline in the percentage of CD4 T-cells expressing (J) CD38+HLA-DR+ and (K) CD38−HLA-DR+. Mean changes from baseline estimated by mixed model analysis are plotted with bars above and below representing 95% confidence intervals. Significance from baseline is shown by error bars that do not bisect the × axis, and is marked with *. When significant differences from baseline were lost upon removal of protocol deviators from the analysis, data from all patients is plotted with * shown. Immunizations are indicated by vertical dashed lines. All immunizations were administered at the time point indicated, after blood was drawn for immunological assessments.
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