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To assess if the reduction in HIV-1 RNA in CD4+ T cells is correlated with the persistence of immune activation following early antiretroviral therapy (ART).Clinical trial (NCT01285050).Next-generation sequencing was used to study total RNA from activated CD4+ T cells (CD38 and human leukocyte antigen - antigen D related (HLA-DR) expressing) collected from 19 treatment-naïve HIV-1/hepatitis C virus-infected patients before and early after ART initiation (≥12 weeks after plasma HIV-1 RNA <50 copies/ml). To validate comparisons, pre and post-ART measures were adjusted for input RNA and overall read number.As expected, ART use was associated with a median [interquartile range (IQR)] 4.3% (2.2–8.3) reduction in the proportion of activated CD4+ T cells (P = 0.0008). Whereas in those activated CD4+ T cells no consistent differences in overall gene expression were detected, interferon-stimulated gene expression declined (P < 2 × 10−16). Pre-ART, sorted activated CD4+ T cells contained a median (IQR) of 959 (252–1614) HIV-1 reads/107 reads compared with 72 (55–152) HIV-1 reads/107 reads after at least 12 weeks of suppressive ART (P = 8 × 10−5). The decrease in HIV-1 reads in activated CD4+ T cells was associated with the change in plasma HIV-1 RNA levels (r = 0.77, P = 2 × 10−4) and the change in the proportion of activated CD4+ T cells (r = 0.70, P = 0.0016).Months of ART led to a marked decrease in cell-associated HIV-1 RNA and interferon-stimulated genes expression in activated CD4+ T cells that were strongly associated with the reduction in the proportion of activated CD4+ T cells.