Immune Activation Is Associated With Increased Gut Microbial Translocation in Treatment-Naive, HIV-Infected Children in a Resource-Limited Setting

Abstract

Background Gut damage resulting in microbial translocation (MT) is considered a major cause of immune activation (IA) in HIV infection, but data in children are limited, particularly in the absence of antiretroviral therapy. Methods Sixty perinatally HIV-infected, antiretroviral therapy–naive children, aged 2–12 years, were evaluated for plasma levels of lipopolysaccharide, DNA sequences encoding bacterial ribosomal 16 second (16S) RNA (16S rDNA) and soluble CD14 concurrently with markers of CD4 and CD8 T-cell IA and immune exhaustion (IE), CD4 counts, and plasma viral load. At study entry, participants were classified into immune categories (ICs): IC1 (CD4% > 25), IC2 (CD4% 15–25), and IC3 (CD4% < 15). Age-matched HIV-uninfected children served as controls. Data were evaluated at study entry and at 12 months. Results Levels of MT, IA, and IE were increased in patients as compared with controls, were highest in patients in IC3 group, and did not change over 12 months. MT products lipopolysaccharide and 16S rDNA correlated with each other and each correlated with plasma viral load, soluble CD14, and T-cell IA and IE. There was a correlation of IA with IE. CD4 counts and percentage were inversely correlated with MT products and underlying CD4 activation. Conclusions In a natural history cohort of HIV-infected children not on therapy, MT was more pronounced in the most severely immunocompromised patients and was associated with IA. Strategies to reduce MT may help to reduce IA and prevent CD4 depletion.

Is impaired kidney function an independent predictor of the risk of myocardial infarction in HIV-infected individuals?

“…This has been observed in HIV-infected adults [10]. Our results support previous observations that HIV-infected children have gut-associated lymphoid tissue injury resulting in persistent microbial translocation and/or defects in LPS clearance mechanisms [11][12][13]15,16].…”

“…During the acute phase of infection, the main driver of immune activation appears to be high levels of virus with other factors such as microbial translocation more important in chronic infection [8]. Few studies have focused on immune activation and microbial translocation profiles of HIVinfected children [11][12][13].…”

Statin modulation of monocyte phenotype and function: implications for HIV-1-associated neurocognitive disorders

“…We saw this effect both in unstimulated monocytes and in cells activated with two stimuli implicated in HAND pathogenesis, LPS and MCP-1. Residual inflammation in ART-treated individuals, believed to be a major contributor to HAND (Yadav and Collman 2009; Chen, Gill et al 2014), is partially driven by persistent translocation of microbial products such as LPS, due to incomplete restoration of damaged gut immune barrier (Jiang, Lederman et al 2009; Pilakka-Kanthikeel, Kris et al 2014). Similarly, MCP-1 is elevated in HIV infection and, in particular, recruits monocytes to tissues (Williams, Calderon et al 2013).…”

Increased Immune Activation and Exhaustion in HIV-infected Youth

“…In addition, data suggest that IE could be critical in the viral persistence that characterizes chronic HIV infection [28]. To date, few studies have investigated IE in HIV-infected children [18, 23]. These studies both demonstrated an increase in IE compared to healthy controls, but only ART-naïve children were included.…”