Microbial Translocation in Immunological Non-Responders to ART

A research letter in the journal AIDS reports that translocation of bacteria across the gut mucosa is associated with a failure to reconstitute CD4 T cells despite viral suppression by antiretroviral therapy (ART). The authors report that plasma levels of lipopolysaccharide (LPS), an indirect measure of microbial translocation, were significantly higher in both immunological non-responders (INRs) and individuals with untreated, advanced HIV infection compared to individuals on ART who experience good CD4 T cell reconstitution. The researchers also offer the first published direct evidence of microbial translocation in HIV infection by measuring bacterial 16s DNA in samples and then conducting sequencing experiments to show that the DNA was derived from gut bacteria species. Using this technique, they found that 16s DNA could be isolated from five out of seven INRs and six out of 12 individuals with advanced, untreated HIV infection but none of the seven individuals with a good CD4 T cell response to ART.

In discussing their results, the authors state: “by showing an association between LPS and bacterial DNA fragments in plasma, our study is the first to directly demonstrate bacterial translocation in both naïve and HAART-treated HIV-infected patients through the direct demonstration of enterobacteria genome sequences.” They also raise the issue of uncertainty regarding cause and effect, noting that microbial translocation may contribute to the lack of an immunological response to ART seen in INRs but also that, conversely, “bacterial translocation might be favoured in INRs by reduced T-cell-mediated competence failing to provide full immune control in mucosa and mesenteric lymph nodes, thus permitting peripheral egress and survival of bacteria.” In support of this possibility, they cite a paper from 1980 showing that microbial translocation occurs in athymic mice and can be reduced when the mice receive thymic grafts. The full text of this paper is available online. Interestingly, this is the same suggestion made by the recent murine study from Brigitta Stockinger’s group which found that reduce naïve T cell levels were associated with microbial translocation and immune activation (reported on the blog previously).

AIDS. 22(15):2035-2038, October 1, 2008.

Research Letters

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

Marchetti, Giulia; Bellistri, Giusi M; Borghi, Elisa; Tincati, Camilla; Ferramosca, Stefania; La Francesca, Maria; Morace, Giulia; Gori, Andrea; Monforte, Antonella d'Arminio

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 <= 200; HIV-RNA <= 50) compared with 11 full responders (CD4+ T-cell >= 400; HIV-RNA <= 50). These data provide novel insight into INRs pathogenesis, since they correlate augmented systemic translocation of microbial bioproducts with T-cell hyperactivation.

Comments

[Ian]

What happens to gammadeltas and other unconventional T cells in HIV infection? There's evidence that they have a role in healing and maintaining the intestinal wall, I think .... I need to look at the papers.