Increased gut microbial translocation in HIV-infected children persists in virologic responders and virologic failures after antiretroviral therapy.

Immune activation is a major component of disease progression in chronic HIV infection and leads to excessive destruction of CD4 T cells by apoptosis, uncontrolled virus replication in activated CD4 T cells and immune exhaustion. Manifestations of immune activation include polyclonal B cell hypergammaglobulinemia, increased T cell turnover, increased frequency of activated T cells and increased levels of proinflammatory cytokines and chemokines [1]. Mechanisms of immune activation have been difficult to pinpoint and were initially attributed to direct and indirect effects of HIV infection [2-4]. Following identification of the gut as a major site of HIV replication with loss of CD4 T cells, Brenchley et al brought attention to the potential role of translocation of microbial products from the gut into the systemic circulation as a causative factor in immune activation in chronically HIV-infected adults [5]. Subsequently, it was shown that loss of TH-17 cells and structural damage to the gut epithelium result in MT and IA [6, 7]. MT involves passage of gut derived microbes and/or microbial products into the systemic circulation without overt bacteremia. MT is assessed by quantifying plasma levels of lipopolysaccharide (LPS), which is a major component of gram-negative bacteria cell walls, or plasma levels of 16SrDNA, which represents the conserved sequences of bacterial DNA fragments common to most bacteria and LPS core antigen [8]. Elevated LPS levels in plasma are indicative of increased intestinal permeability and occur after invasive gastrointestinal surgery [9], in graft-versus-host disease and in inflammatory bowel disease [10]. In adults with chronic HIV infection, levels of plasma LPS in “progressors” are increased as compared to non-progressors or uninfected individuals, and have been correlated with activated CD8 T cells expressing increased CD38 molecules and with sCD14, indicating monocyte activation [5]. Monocytes and macrophages express membrane CD14 and secrete soluble CD14 (sCD14) upon activation. Measurement of plasma sCD14 provides evidence for direct chronic LPS stimulation of monocytes and macrophages in vivo. More recently, LPS in plasma was found to be correlated with 16SrDNA, CD8 T cell immune activation and with sCD14, a marker of monocyte activation [5, 11-13]. In patients on potent antiretroviral therapy (ART), persistent IA and ongoing evidence of microbial translocation, despite virologic control, has been linked to impaired CD4 T cell reconstitution [14]. In HIV-infected children data on MT is limited and has been derived mainly from the LPS assay. Interestingly, two studies in ART naive children documented high LPS levels which did not correlate with immune activation and LPS levels did not decrease after potent ART even in patients who controlled virus replication [15, 16]. These findings differ from data in HIV-infected adults and also differ by their lack of correlation with CD4 T cell immune reconstitution. In both pediatric studies, active thymus output was credited for replenishing the CD4 T cells. Because IA is such an important aspect of HIV disease, investigation of IA in different clinical scenarios could enhance our understanding of underlying mechanisms. The present study investigated a set of prospectively collected plasma samples from a completed PACTG study (P338) in which ART experienced, immunologically stable but viremic HIV infected children were given a protease inhibitor (PI) based regimen or dual nucleosides. As the outcome on HIV virus burden and T cell immune activation was known [17], we tested the hypothesis that gut microbial translocation is a major stimulus for immune activation that persists after control of virus replication. In the present study, we show that gut MT persists after control of virus replication and is associated directly or indirectly with generalized immune activation. Further we found that IA was linked to MT rather than virus load in patients who failed to control virus replication on ART.