Abstract
Background:We aimed to describe the mechanisms of immunological recovery and the effects of blocking CCR5 in patients starting ART with advanced HIV-infection.Methods:This was a sub-study of a 48 week double-blind, clinical trial where patients starting ART with CD4+ cell counts <100 cells/uL were randomized to receive maraviroc or a placebo. CD4+ and CD8+ cell maturation phenotypes, expression of PD-1 and CCR5, and activation indices were measured at weeks 0, 4, 12, 24, and 48. The reactivity of CD4+ and CD8+cells with peptides of CMV and MTb, and with Staphylococcal enterotoxin B (SEB) was assessed by intra-cellular expression of IFNγ, TNFα, and CD40 ligand at weeks 0, 4, and 12 of ART.Results:Forty patients were included in the study (Maraviroc = 22; placebo = 18). Sustained increases in CD8+ cells and in proportions of CCR5+ CD4+ and CD8+ cells were observed in the maraviroc arm. Early increases in the proportions of activated (CD38+, HLA-DR+), PD-1+ CD4+, and CD8+ cells and more matured CD8+ cells, were observed in the maraviroc arm. T cell responses to CMV, MTb, and SEB did not differ by treatment arms.Conclusions:During antiretroviral therapy in advanced HIV infection, maraviroc retains mature, activated CCR5+ cells in circulation without impact on CD4+ T cell recovery or T cell reactivity to antigen or superantigen.
Highlights
HIV-infected patients with very low CD4+ cell counts who are beginning combination antiretroviral therapy (ART) remain at risk for AIDS-defining opportunistic infections (ADEs) after ART initiation, immune response inflammatory syndrome (IRIS), and early mortality [1,2,3,4,5,6]
Cardiovascular, and neoplastic non-AIDS defining illnesses leading to late mortality has been associated with low CD4+ counts at ART initiation [7,8,9,10]
We found that maraviroc was associated with an early increase of CCR5+ cells in the circulation, leading to increases of peripheral activated T cells as well as more mature CD8+ cells
Summary
HIV-infected patients with very low CD4+ cell counts who are beginning combination antiretroviral therapy (ART) remain at risk for AIDS-defining opportunistic infections (ADEs) after ART initiation, immune response inflammatory syndrome (IRIS), and early mortality [1,2,3,4,5,6]. A slow and steady increase in CD4+ cell counts is driven mostly by increasing numbers of “naive” CD4+ cells while CD8+ cells remain elevated in most patients [15,16,17,18,19]. These changes are accompanied by decreases in immune activation markers in memory and naive CD4+ cells, but among memory CD8+ cells [17, 18, 20]. We aimed to describe the mechanisms of immunological recovery and the effects of blocking CCR5 in patients starting ART with advanced HIV-infection
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