Abstract
The 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.
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•Ratio of Serratia to other bacterial genera changes rapidly over time after ART•High ratio at year one drives inflammation and first wave of immune reconstitution•Diversity & distinct microbial ratio at year two is associated with reconstitution•Microbial diversity and composition drive reconstitution in diverse HIV cohorts
Longitudinal high-dimensional analysis of translocated microbial products in the plasma of HIV+ individuals treated with combined antiretroviral therapy reveals dynamic changes in plasma cytokines and immune cell subsets, resulting in two distinct waves of immune reconstitution that lead to CD4+ T cell recovery.
