show Abstracthide AbstractThe impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways driven by changes in the abundance ratio of Serratia to other bacterial genera. Increased CD4 T cell numbers over the first year were associated with high Serratia abundance, pro-inflammatory innate cytokines, and metabolites that drive Th17 gene expression signatures and restoration of mucosal integrity. Subsequently, decreased Serratia abundance and downregulation of innate cytokines allowed re-establishment of systemic T cell homeostasis promoting restoration of Th1 and Th2 gene expression signatures. Analyses of three other geographically distinct cohorts of treated HIV infection established a more generalized principle that changes in diversity and composition of translocated microbial species influence systemic inflammation and consequently CD4 T cell recovery. Overall design: Primary cohort: A total of 11 treatment-naive HIV-infected individuals were recruited at the Joint Clinical Research Center (JCRC) in Kampala Uganda. All participants had detectable plasma HIV viremia and no prior antiretroviral therapy (ART). Combination ART was started at baseline with blood samples collected longitudinally (at months 0, 3, 4, 9, 12 and 24) for pathogen sequencing and immune cell subset RNA sequencing (sorted monocytes and T cells at months 0, 3, 12, 24). Secondary cohorts: Plasma sample collection and pathogen sequencing were done on three independent HIV cohorts with a total of 109 participant timepoints with known T cell counts were assessed in our study. The second Ugandan cohort consisted of 7 HIV uninfected, 10 HIV-infected on cART and 3 paired HIV-infected off cART. The Montreal cohort (Morou et al., 2019) consisted of 6 HIV uninfected and 28 HIV-infected, of which 5 were elite controllers, 3 viremic progressors of which 1 with a paired post-cART timepoint, 12 chronic progressors pre-cART of which 8 with paired post-cART timepoint. The Cleveland cohort (Lederman et al., 2011) consisted of HIV-infected persons on cART, with 11 immune responders and 44 immune non-responders. Across cohorts, cART participant timepoints were 1-3 years post treatment initiation.