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.
Highlights
The CCR5 antagonist Maraviroc (MVC) which prevents HIV-1 entry into target CD4+ C-C chemokine receptor type 5+ (CD4+ CCR5+) cells, is well tolerated and approved as a combination antiretroviral therapy component [1,2]
CCR5 plays a role in immune activation and lymphocyte recruitment [3]
Study Design A double-blind placebo-controlled trial in HIV-1+ subjects investigating the impact of the addition of MVC 150 mg twice daily (b.i.d. [bis in die]) to ongoing successful ritonavir-boosted protease inhibitor (PI/r)-based combination antiretroviral therapy (cART), on immune function (Figure 1)
Summary
The CCR5 antagonist Maraviroc (MVC) which prevents HIV-1 entry into target CD4+ C-C chemokine receptor type 5+ (CD4+ CCR5+) cells, is well tolerated and approved as a combination antiretroviral therapy (cART) component [1,2]. CCR5 plays a role in immune activation and lymphocyte recruitment [3]. Individuals homozygous for the CCR5∆32 mutation show reduced immune activation, lower production of interleukin-2 (IL-2) and resistance to HIV-1 infection [4,5,6], CCR5–/– mice display significantly lower delayed type hypersensitivity (DTH) than those expressing CCR5 [7]. Immune hyperactivation, skewed T-cell differentiation, senescence, exhaustion, anergy and loss of functionality are hallmarks of progressive HIV-1 infection [8,9,10,11,12,13]. MVC may have immunomodulatory properties, potentially facilitating immunological improvement toward normality, when added to successfully suppressive cART [1,13].
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