Gut epithelial barrier dysfunction, innate immune activation, inflammation, and coagulation-but not T-cell activation, senescence, and exhaustion-independently predict mortality in individuals with treated HIV infection with a history of AIDS and are viable targets for interventions.

Immune activation that appears related to exposure to microbial elements distinguishes immune failure from immune success in treated HIV infection.

NCT01218802.

Key Points• Maraviroc intensification unexpectedly increases T-cell activation in peripheral blood and rectal mucosa during treated HIV infection.• Maraviroc appears to redistribute CD81 T cells from the gut to peripheral blood during treated HIV infection.The CCR5 inhibitor maraviroc has been hypothesized to decrease T-cell activation in HIVinfected individuals, but its independent immunologic effects have not been established in a placebo-controlled trial. We randomized 45 HIV-infected subjects with CD4 counts <350 cells per mm 3 and plasma HIV RNA levels <48 copies per mL on antiretroviral therapy (ART)to add maraviroc vs placebo to their regimen for 24 weeks followed by 12 weeks on ART alone. Compared with placebo-treated subjects, maraviroc-treated subjects unexpectedly experienced a greater median increase in % CD381HLA-DR1 peripheral blood CD81 T cells at week 24 (12.2% vs 20.7%, P 5 .014), and less of a decline in activated CD41 T cells (P < .001). The % CD381HLA-DR1 CD41 and CD81 T cells increased nearly twofold in rectal tissue (both P < .001), and plasma CC chemokine receptor type 5 (CCR5) ligand (macrophage-inflammatory protein 1b) levels increased 2.4-fold during maraviroc intensification (P < .001). During maraviroc intensification, plasma lipopolysaccharide declined, whereas sCD14 levels and neutrophils tended to increase in blood and rectal tissue. Although the mechanisms explaining these findings remain unclear, CCR5 ligandmediated activation of T cells, macrophages, and neutrophils via alternative chemokine receptors should be explored. These results may have relevance for trials of maraviroc for HIV preexposure prophylaxis and graft-versus-host disease. This trial was registered at www.clinicaltrials.gov as #NCT00735072. (Blood. 2013;121(23):4635-4646)