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. 2020 Apr 24;5(1):68-88.
doi: 10.20411/pai.v5i1.363. eCollection 2020.

Biomarkers of Cellular Stress Do Not Associate with sCD14 in Progressive HIV and SIV Infections in Vivo

Carol L Vinton  1 , Carly E Starke  1 , Alexandra M Ortiz  1 , Stephen H Lai  1 , Jacob K Flynn  1 , Ornella Sortino  2 , Kenneth Knox  3 , Irini Sereti  2 , Jason M Brenchley  1
Affiliations

Biomarkers of Cellular Stress Do Not Associate with sCD14 in Progressive HIV and SIV Infections in Vivo

Carol L Vinton et al. Pathog Immun. .

Abstract

Background: Microbial translocation occurs after damage to the structural and/or immunological barrier of the gastrointestinal (GI) tract into circulation. Microbial components that trans-locate from the lumen of the GI tract directly stimulate the immune system and contribute to inflammation. When microbial translocation becomes chronic, the inflammation has detrimental consequences. Given that microbial translocation is an important phenomenon in many diseases, defining biomarkers that reliably reflect microbial translocation is critical. Measurement of systemic microbial products is difficult since: 1) robust assays to measure microbial antigens simultaneously are lacking; 2) confounding factors influence assays used to detect microbial products; and 3) biological clearance mechanisms limit their detection in circulation. Thus, host proteins produced in response to microbial stimulation are used as surrogates for microbial translocation; however, many of these proteins are also produced in response to host proteins expressed by dying cells.

Methods: We measured plasma levels of biomarkers associated with GI tract damage, immune responses to microbial products, and cell-death in people living with HIV before and after antiretroviral administration, and in macaque nonhuman primates before and after SIV infection.

Results: Proteins secreted during cellular stress (receptor for advanced glycation endproducts-RAGE and high motility group box 1-HMGB1), which can induce sCD14 production in vitro and in vivo, do not associate with elevated levels of biomarkers associated with microbial translocation in progressively HIV-infected individuals and SIV-infected NHPs.

Conclusions: Bystander cell death and generalized inflammation do not contribute to elevated levels of sCD14 observed in HIV/SIV-infected individuals.

Keywords: HIV; Microbial translocation; SIV; inflammation.

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Conflict of interest statement

Irini Sereti and Jason M. Brenchley serve as associate editors for Pathogens and Immunity.

Figures

Figure 1.
Figure 1.
Plasma biomarker levels in NHPs during SIV infection and in people living with HIV (PLWH) following ART. (A-E) Plasma levels of biomarker analytes in NHPs (n = 20, graphs on the left, with PTs in blue and RMs in red) pre-SIV infection, during acute-SIV infection, and during chronic infection; and PLWH (n = 34, graphs on the right) pre- and post-ART treatment for (A) sCD14, (B) HMGB1, (C) RAGE, (D) IFABP, (E) Zonulin, and (F) Reg3α. Lines connect the same study participant over time. Wilcoxon t tests were used to determine each P-value. Δ values represent the mean fold-change between timepoints.
Figure 2.
Figure 2.
Plasma biomarker associations. (A-I) Correlational analyses between longitudinal changes in plasma biomarkers in humans (black), RMs (red), and PTs (blue). All associations were analyzed using the Spearman rank test.
Figure 3.
Figure 3.
Plasma biomarker associations with CD4 T cell frequencies. (A-E) Correlational analyses between changes in CD4+ T cell numbers in peripheral blood and changes in plasma biomarkers in humans (black), RMs (red), and PTs (blue) for (A) sCD14, (B) HMGB1, (C) RAGE), (D) IFABP, and (E) Zonulin. All associations were analyzed using the Spearman rank test.
Figure 4.
Figure 4.
Plasma biomarker associations with plasma viral load. (A-E) Correlational analyses between SIV or HIV plasma viral load during chronic infection and plasma biomarkers in humans (black), RMs (red), and PTs (blue) for (A) sCD14, (B) HMGB1, (C) RAGE), (D) IFABP, and (E) Zonulin. All associations were analyzed using the Spearman rank test.
See this image and copyright information in PMC

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