Endotoxemia Is Associated with Altered Innate and Adaptive Immune Responses in Untreated HIV-1 Infected Individuals

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.

Shift in Monocyte Apoptosis with Increasing Viral Load and Change in Apoptosis-Related ISG/Bcl2 Family Gene Expression in Chronically HIV-1-Infected Subjects

“…Change in ISG expression and increasing sCD14 with viremia may evidence increasing microbial translocation, as microbial products were associated with interferon alpha activation in HIV-1 viremic patients (17) and may contribute to the shift in monocyte ISG expression and apoptosis induction (64,65). Previous studies have demonstrated elevated sCD14 in multiple comparisons of HIV ϩ to HIV Ϫ donors (14,16,17,(66)(67)(68), and while we demonstrated an association with viral load and CD4 count ( Fig. 3C; see also Fig.…”

Effect of Solar Particle Event Radiation and Hindlimb Suspension on Gastrointestinal Tract Bacterial Translocation and Immune Activation

“…This includes an increase in anti-inflammatory cytokines and a decrease in TNF-α in LPS stimulated spleen cells [60], reductions in interferon-γ and IL-2 following PMA and ionomycin stimulation of peripheral blood cells of astronauts [15], and reduced NK cell number and functionality [13], [14]. These alterations to immune function are very similar to those observed in settings of increased immune activation caused by exposure to pathogen associated molecular patterns (PAMPs), such as LPS [61], [62], [63], [64], [65], [66]. Specific examples include; a reduction in proinflammatory cytokine production by myeloid cells [66], [67], a reduction in antigen-specific T cell effector cytokine responses [61], and a reduction in circulating NK cells [68].…”

Biological effects of space radiation and development of effective countermeasures

“…The changes in responses brought about by exposure to PAMPs are known as “tolerance”, in which subsequent responses are reduced in quality and quantity, which is thought to protect the host by limiting excessive inflammation and preventing septic shock (166, 169). As has been observed in many different disease states (154, 162,163, 170–173), continuous or extended exposure to PAMPs can lead to long-lived immune dysfunction. This condition may exist during space flight, as LBP, a well-known marker of immune activation, is known to be elevated in astronauts’ plasma (159, 167).…”