Abstract
BackgroundMicrobial translocation may contribute to the immunopathogenesis in HIV infection. We investigated if microbial translocation and inflammation were associated with innate and adaptive immune responses in adults with HIV.Methodology/Principal FindingsThis was an observational cohort study. Sera from HIV-infected and HIV-uninfected individuals were analyzed for microbial translocation (soluble CD14, lipopolysaccharides [LPS], endotoxin core antibody, and anti-α-galactosyl antibodies) and inflammatory markers (high sensitivity C-reactive protein, IL-6, IL-1 receptor antagonist, soluble tumor necrosis factor receptor II, and IL-10) with enzyme-linked immunosorbent assays. Peripheral blood mononuclear cells (PBMC) from HIV-infected persons and healthy controls (primed with single-stranded HIV-1-derived RNA) were stimulated with LPS, and cytokine production was measured. Finally, HIV-infected patients were immunized with Prevnar 7vPnC±CpG 7909 followed by Pneumo Novum PPV-23. Effects of microbial translocation and inflammation on immunization were analyzed in a predictive regression model. We included 96 HIV-infected individuals, 76 on highly active antiretroviral therapy (HAART), 20 HAART-naive, and 50 healthy controls. Microbial translocation and inflammatory markers were higher among HIV-infected persons than controls. Cytokine levels following LPS stimulation were increased in PBMCs from HAART-naive compared to HAART-treated HIV-infected persons. Further, RNA-priming of PBMCs from controls acted synergistically with LPS to augment cytokine responses. Finally, high serum LPS levels predicted poor vaccine responses among HAART-naive, but not among HAART-treated HIV-infected individuals.Conclusions/SignificanceLPS acts synergistically with HIV RNA to stimulate innate immune responses in vitro and increasing serum LPS levels seem to predict poor antibody responses after vaccination among HAART-naive HIV-infected persons. Thus, our results suggest that microbial translocation may be associated with innate and adaptive immune dysfunction in untreated HIV infection.
Highlights
Untreated HIV infection is characterized by progressive immune dysfunction
Microbial translocation in HIV-infected individuals Soluble CD14 levels were significantly higher in HIV-infected subjects (6.58 mg/mL, interquartile ranges (IQR): 4.88–9.47) than in controls (3.12 mg/mL, IQR: 2.76–3.66, p,0.001), and there was a trend towards higher LPS in HIV-infected subjects (1.67 EU/mL, IQR: 1.30–2.06) compared to controls (1.43 EU/mL, IQR: 1.14–1.88, p=0.06) (Fig. 1A and B)
A near-significant correlation was observed between soluble CD14 (sCD14) and sTNF-rII in HIV-infected subjects (p=0.053, rho=0.20), but we found no associations between sCD14 and the other pro-inflammatory markers, or between LPS and any of the pro-inflammatory markers in either of the groups, except IL-10 in highly active antiretroviral therapy (HAART)-naive subjects (p,0.01, rho=20.57)
Summary
Untreated HIV infection is characterized by progressive immune dysfunction. This, in turn, leads to elevated levels of pro-inflammatory cytokines, increased apoptosis of epithelial cells, and altered tight junction protein composition [4] resulting in a functional degradation of the intestinal barrier [5]. These events are thought to induce microbial translocation, an enhanced transit of microbial products through intestinal mucosa to the blood stream. Microbial translocation may contribute to the immunopathogenesis in HIV infection.
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