Are Plasma Biomarkers of Immune Activation Predictive of HIV Progression: A Longitudinal Comparison and Analyses in HIV-1 and HIV-2 Infections?

Abstract

BackgroundChronic immune activation is a hallmark of HIV infection and has been associated with disease progression. Assessment of soluble biomarkers indicating immune activation provide clues into pathogenesis and hold promise for the development of point-of-care monitoring of HIV in resource-poor-settings. Their evaluation in cohort resources is therefore needed to further their development and use in HIV research.Methodology/Principal FindingsLongitudinal evaluation of βeta-2 microglobulin (β-2 m), neopterin and suPAR soluble urokinase-type plasminogen activator receptor (suPAR) was performed with archived plasma samples to predict disease progression and provided the first direct comparison of levels in HIV-1 and HIV-2 infections. At least 2095 samples from 137 HIV-1 and 198 HIV-2 subjects with starting CD4% of ≥28 and median follow up of 4 years were analysed. All biomarkers were correlated negatively to CD4% and positively to viral load and to each other. Analyses in subjects living for ≥5 years revealed increases in median β-2 m and neopterin and decreases in CD4% over this period and the odds of death within 5 years were positively associated with baseline levels of β-2 m and neopterin. ROC analyses strengthened the evidence of elevation of biomarkers in patients approaching death in both HIV-1 and HIV-2 infections. Regression models showed that rates of biomarker fold change accelerated from 6–8 years before death with no significant differences between biomarker levels in HIV-1 and HIV-2 at equal time points prior to death.An ‘immune activation index’ analysis indicative of biomarker levels at equivalent viral loads also showed no differences between the two infections.Conclusions/SignificanceOur results suggest that β-2 m and neopterin are useful tools for disease monitoring in both HIV-1 and HIV-2 infections, whereas sUPAR performed less well. Levels of immune activation per amount of virus were comparable in HIV-1 and HIV-2 infected subjects.

Protection Versus Pathology in Aviremic and High Viral Load HIV-2 Infection—The Pivotal Role of Immune Activation and T-cell Kinetics

“…Immune activation was the strongest predictor of T-cell turnover in both CD4 + and CD8 + populations (Supplementary Figure 2). This is consistent with the observation that, at similar clinical disease stages, HIV-1- and HIV-2-infected subjects demonstrate similar levels of immune activation [21, 39]. Our data add subset specificity to this paradigm; for example, naive CD8 + T-cells are even more activated by HIV-2 viremia than by HIV-1 (Figure 1 B ), consistent with poor outcomes at viral loads about 1 log 10 lower in HIV-2 infection [9].…”

Proteomic landscape of bronchoalveolar lavage fluid in human immunodeficiency virus infection

“…In contrast, beta-2 microglobin (B2M) was significantly upregulated in HIV ϩ BALF compared with uninfected individuals. Elevated plasma levels of this major histocompatibility complex class I-associated protein have been linked with HIV disease progression (3,29), and in vitro models suggest that B2M suppresses immune responsiveness of dendritic cells (45). Secretory leukocyte protease inhibitor (SLPI) was another differentially upregulated BALF protein in HIV ϩ subjects that interacts with HIV-1 env protein.…”

Correlation of (1→3)-β-D-glucan with other inflammation markers in chronically HIV infected persons on suppressive antiretroviral therapy

“…Such microbial translocation most likely leads to local and systemic immune activation, characterized by increased levels of pro-inflammatory cytokines such as tumour-necrosis-factor α (TNF-α), neopterin, cluster of differentiation 14 (CD14), interleukin-8 (IL-8), and interleukin-6 (IL-6) [6], [7], [8], [9]. In particular, plasma neopterin is an established marker of monocyte activation and was repeatedly associated with HIV disease progression, greater peripheral monocyte HIV DNA reservoirs and negative neurocognitive and cardiovascular outcomes [10], [11], [12]. …”