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

Samantha J. Westrop; Graeme Moyle; Akil Jackson; Mark Nelson; Sundhiya Mandalia; Nesrina Imami

doi:10.2119/molmed.2012.00206

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

Samantha J. Westrop
, Graeme Moyle
, Akil Jackson
, Mark Nelson
, Sundhiya Mandalia
, Nesrina Imami

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1240-1248
Number of pages	9
Journal	Molecular Medicine
Volume	18
Issue number	8
DOIs	https://doi.org/10.2119/molmed.2012.00206
Publication status	Published - Aug 2012
Externally published	Yes

Bibliographical note

Funding Information:
Patients provided written informed consent prior to study entry, after which eligibility was assessed according to inclusion and exclusion criteria (Figure 2). The study was conducted according to Good Clinical Practice guidelines (22), in accordance with the Declaration of Helsinki (23), approved by UK ethics committee (Riverside Research Ethics Committee, NHS Health Research Authority, Bristol, UK), funded and sponsored by St Stephen’s AIDS Trust (SSAT), with an unrestricted grant from Pfizer Inc. (New York, NY, USA).

Funding Information:
We wish to thank the patients and staff of the Saint Stephen’s Center, without whom this study would not have been possible. This study was funded and sponsored by SSAT, with an unrestricted grant from Pfizer Inc. awarded to G Moyle and N Imami. N Imami also was supported by funding from the Medical Research Council (MRC) (grant number G0501957). All authors have no relevant financial interests to disclose. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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10.2119/molmed.2012.00206

Cite this

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title = "CCR5 antagonism impacts vaccination response and immune profile in HIV-1 infection",

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.",

author = "Westrop, \{Samantha J.\} and Graeme Moyle and Akil Jackson and Mark Nelson and Sundhiya Mandalia and Nesrina Imami",

note = "Funding Information: Patients provided written informed consent prior to study entry, after which eligibility was assessed according to inclusion and exclusion criteria (Figure 2). The study was conducted according to Good Clinical Practice guidelines (22), in accordance with the Declaration of Helsinki (23), approved by UK ethics committee (Riverside Research Ethics Committee, NHS Health Research Authority, Bristol, UK), funded and sponsored by St Stephen{\textquoteright}s AIDS Trust (SSAT), with an unrestricted grant from Pfizer Inc. (New York, NY, USA). Funding Information: We wish to thank the patients and staff of the Saint Stephen{\textquoteright}s Center, without whom this study would not have been possible. This study was funded and sponsored by SSAT, with an unrestricted grant from Pfizer Inc. awarded to G Moyle and N Imami. N Imami also was supported by funding from the Medical Research Council (MRC) (grant number G0501957). All authors have no relevant financial interests to disclose. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.",

year = "2012",

month = aug,

doi = "10.2119/molmed.2012.00206",

language = "English",

volume = "18",

pages = "1240--1248",

journal = "Molecular Medicine",

issn = "1076-1551",

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T1 - CCR5 antagonism impacts vaccination response and immune profile in HIV-1 infection

AU - Westrop, Samantha J.

AU - Moyle, Graeme

AU - Jackson, Akil

AU - Nelson, Mark

AU - Mandalia, Sundhiya

AU - Imami, Nesrina

N1 - Funding Information: Patients provided written informed consent prior to study entry, after which eligibility was assessed according to inclusion and exclusion criteria (Figure 2). The study was conducted according to Good Clinical Practice guidelines (22), in accordance with the Declaration of Helsinki (23), approved by UK ethics committee (Riverside Research Ethics Committee, NHS Health Research Authority, Bristol, UK), funded and sponsored by St Stephen’s AIDS Trust (SSAT), with an unrestricted grant from Pfizer Inc. (New York, NY, USA). Funding Information: We wish to thank the patients and staff of the Saint Stephen’s Center, without whom this study would not have been possible. This study was funded and sponsored by SSAT, with an unrestricted grant from Pfizer Inc. awarded to G Moyle and N Imami. N Imami also was supported by funding from the Medical Research Council (MRC) (grant number G0501957). All authors have no relevant financial interests to disclose. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

PY - 2012/8

Y1 - 2012/8

N2 - 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.

AB - 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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ER -

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

Abstract

Bibliographical note

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