Abstract
In advanced HIV infection, the homeostatic balance between gastrointestinal indigenous bacteria and gut immunity fails and microbes are able to overcome the intestinal barrier and gain the systemic circulation. Because microbial translocation is not fully controlled by antiviral therapy and is associated with inefficient CD4+ reconstitution, we investigated the profile of translocating bacteria in peripheral blood of 44 HIV-infected patients starting therapy with advanced CD4+ T-lymphopenia and displaying poor CD4+ recovery on virologically suppressive HAART. According to CD4+ reconstitution at 12-months HAART, patients were considered Partial Immunological Responders, PIRs (CD4+≥250/µl, n = 29) and Immunological non Responders, INRs (CD4+<200/µl, n = 15)). We show that PIRs and INRs present similarly elevated plasma levels of lipopolysaccharide (LPS) and its ligand sCD14 that were not lowered by virologically suppressive therapy. Bacterial 16S rRNA gene amplification and sequencing resulted in a highly polymicrobic peripheral blood microbiota both prior and after 12-month HAART. Several differences in bacterial composition were shown between patients' groups, mainly the lack of probiotic Lactobacillaceae both prior and after therapy in INRs. Failure to control microbial translocation on HAART is associated with a polymicrobic flora circulating in peripheral blood that is not substantially modified by therapy.
Highlights
A substantial breach of the anatomo-functional GI barrier occurs, with progressive failure of mucosal immunity and leakage into the systemic circulation of bacterial by-products, such as lipopolysaccharide (LPS) and bacterial DNA fragments, which contribute to systemic immune activation [1] [4,5,6]
Through the joint quantification of gut-derived bacterial macromolecules and genotypes, we hereby assessed the quality of microbial translocation in peripheral blood of HIV-infected patients starting Highly active antiretroviral therapy (HAART) with severe immune depression and lacking CD4+ recovery on therapy, and have made the following observations
HIVinfected patients maintaining heightened microbial translocation on virologically-suppressive HAART display a circulating microbiota that is polymicrobic at the genotype level and that is not substantially modified by therapy
Summary
HIV infection causes dramatic damage to the gastrointestinal (GI) tract, that includes substantial disruption of gut microbiota composition with presence of microbes at higher pathogenic potential compared to less aggressive indigenous organisms, massive loss of gut-residing CD4+ T-cells, and down-regulation of GI tract genes expression [1,2,3].a substantial breach of the anatomo-functional GI barrier occurs, with progressive failure of mucosal immunity and leakage into the systemic circulation of bacterial by-products, such as lipopolysaccharide (LPS) and bacterial DNA fragments, which contribute to systemic immune activation [1] [4,5,6].Highly active antiretroviral therapy (HAART) only partially amends GI tract antomo-functional damage [1,7] and intestinal microbiota, further hampering intestinal homeostasis [8] and sustaining microbial translocation [9,10]. A substantial breach of the anatomo-functional GI barrier occurs, with progressive failure of mucosal immunity and leakage into the systemic circulation of bacterial by-products, such as lipopolysaccharide (LPS) and bacterial DNA fragments, which contribute to systemic immune activation [1] [4,5,6]. Circulating microbial products have been shown to decrease during HAART, they remain elevated, in turn affecting immune restoration [1,4,7]. Elevated microbial translocation as well as failure to contain it in the course of virologicallysuppressive HAART have been associated to an increased risk of HIV disease progression and death [7,12]
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