Effect of Antiretroviral Therapy on Damage-Associated Molecular Patterns (DAMPs). Lipopolysacharide (LPS) and Immune Reconstitution in HIV-Infected Individuals

Thesis (Master's)--University of Washington, 2015BACKGROUND: Even with successful antiretroviral therapy (ART), HIV infection is still accompanied by ongoing chronic immune activation and inflammation that may impact ART-mediated immune reconstitution. The mechanisms of this immune activation are not completely defined. Damage-associated molecular patterns (DAMPs) are endogenous innate immune activators that have not been well studied in HIV-infected persons. METHODS: We conducted a quasi-experimental pre-post observational study of two DAMPs (HMGB1 and S100A9) and a marker of microbial translocation (LPS) in samples collected from research participants before and at least 2 years after initiation of continuously suppressive ART. Differences in mean biomarker levels were assessed using paired t-tests. Correlation between biomarker levels were assessed using Pearson correlation coefficients for normal data and Spearman's rho for non-normal data. Multivariate linear regression was used to assess association between biomarker values and clinical outcomes after suppressive ART. RESULTS: Mean HMGB1 levels increased between pre- and post-ART samples (1.95 ng/mL vs. 3.02 ng/mL, p=0.01) and the proportion of individuals with detectable S100A9 increased significantly (p=0.01). We detected no change in mean LPS levels with effective ART (p=0.85). Neither LPS, HMGB1, nor S100A9 was associated with baseline CD4 or viral load or degree of CD4 reconstitution with effective ART-mediated viral suppression. CONCLUSIONS: DAMPs do not appear to be significantly associated with CD4 count, viral load, or degree of CD4 reconstitution after virologic suppression. Increased HMGB1 levels after suppressive ART may be a non-specific marker of inflammation and hence subject to confounding by other conditions