Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy

Abstract

Patients with inefficient CD4+ T-cell recovery on virogically suppressive highly active antiretroviral therapy constitute a major clinical hurdle given the threat of HIV/AIDS disease progression. We show heightened circulating lipopolysaccharide associated with plasma enterobacterial DNA and highly activated Ki67+CD4+CD8+ in 24 immunologic-nonresponders (CD4+ T-cell < or = 200; HIV-RNA < or = 50) compared with 11 full responders (CD4+ T-cell > or= 400; HIV-RNA < or = 50). These data provide novel insight into INRs pathogenesis, since they correlate augmented systemic translocation of microbial bioproducts with T-cell hyperactivation.

Microbial Translocation in the Pathogenesis of HIV Infection and AIDS

“…Particularly, HIV-infected patients in an advanced stage of disease (Ͻ200 CD4 ϩ T cells/ml) had significantly higher plasma LPS levels than uninfected individuals, thus suggesting the presence of increased microbial translocation in this study population. Interestingly, a positive correlation was found between LPS levels in plasma and measures of innate and adaptive immune activation (33,39), thus supporting the hypothesis that microbial translocation may result in T-cell activation, which is known to influence HIV disease progression (5,11,12,58). Table 2 shows an overview of studies suggesting that microbial translocation through the gastrointestinal tract is a cause of immune activation and immune dysfunction in HIV/SIV infections.…”

“…Most interestingly, the total bacterial load in the stools negatively correlated with duodenal T-cell activation, and levels of Enterobacteriales and Bacteroidales fecal DNA were significantly associated with CD4 ϩ T-cell loss in the duodenum and peripheral CD8 ϩ T-cell activation, respectively (64). Therefore, by correlating specific features of the gut microbiome and markers of HIV disease progression, these data provide evidence for a direct role of the gut microbiome in driving local and systemic immune activation in HIV-infected patients (39,45).…”

“…The majority of 16S rRNA gene PCR assays are designed for the qualitative detection of amplicons, which allows for the identification of different bacterial species (39,40,50). Novel and highly sensitive real-time PCRs have recently been developed, focusing on the accurate quantification of 16S rRNA gene sequences (45,46,51,52).…”

“…Circulating levels of LPS have been consistently reported to decrease after the initiation of ART, even though they did not return to the levels observed for healthy HIV-uninfected individuals (33,39,45,62,65). Since persistent immune activation has long been implicated as a factor impairing the immunological response to ART (13,14), the question as to whether microbial translocation might affect immune recovery after ART has been investigated by different groups in the last few years.…”

Heart–Lung Interaction via Infection

“…Bacterial translocation from the GI tract to the peripheral circulation has been extensively studied in HIV infection, but is also common in liver disease and other conditions (24)(25)(26)(27). Translocation occurs early in HIV infection due to depletion of gut CD41 lymphocytes and is not completely eradicated by ART, particularly in patients with a suboptimal CD4 cell count or HIV viral level responses (25,28). Persistent systemic exposure to bacterial antigens from MT triggers immune activation and inflammation in HIVinfected adults (25,26).…”