Surrogate Biomarkers of Disease Progression in Human Pegivirus Seropositive Human Immunodeficiency Virus-Infected Individuals

Abstract

Scientific observations indicate that an actively prevailing systemic condition could alleviate the pathology of another disease. Human pegivirus (HPgV), a highly ubiquitous flavivirus is believed to be associated with slow human immunodeficiency virus (HIV) disease progression, and has seldom been linked to hepatic pathology. In this study, we investigated whether HPgV seropositivity had any impact on surrogate markers of HIV disease progression in a cohort of HIV-infected HPgV seropositive (n = 28) and seronegative (n = 12) individuals who were prospectively evaluated for absolute CD4+ T cell counts, plasma viral load (PVL), liver enzymes, and plasma cytokine levels. The HIV PVL was relatively lower in HPgV seropositive than in HPgV seronegative HIV-infected subjects. Clinical markers of hepatic injury were significantly low among HPgV seropositive HIV-infected participants. HPgV seropositive individuals showed significantly higher levels of interleukin-7 (IL-7), and although not significant, the levels of IL-6 were lower among HPgV seropositive subjects. Spearman correlation analysis showed that the absolute CD4+T cell count was inversely correlated with HIV PVL. Exposure to HPgV appears to have a positive prognostic impact on the levels of surrogate biomarkers of HIV disease progression.

Keywords: HIV; HPgV; cytokines; liver enzymes; plasma viral load.

FIG. 1.

Comparison of the HIV PVL, liver transaminases and levels of chemokines/cytokines among HIV-infected HPgV seropositive and seronegative individuals. (A) HIV PVL and liver enzymes, (B) innate cytokines, (C) monocyte-derived cytokines, and (D) T cell-derived cytokines. The Kruskal–Wallis test and post hoc Mann–Whitney U tests were subsequently performed with a Kruskal–Wallis test p-value of <0.05. p-Values <0.05 are considered significant; *p < 0.05, **p < 0.01, ***p < 0.001. G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HIV, human immunodeficiency virus; HPgV, human pegivirus; IFN-γ, interferon-gamma; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; MIP-1β, macrophage inflammatory protein-1 beta; PVL, plasma viral load; TNF-α, tumor necrosis factor alpha.

FIG. 2.

Correlation between chemokines/cytokines, HIV PVL, absolute CD4+ T cell counts, and liver transaminases. (A) Spearman correlation of plasma HIV viral load and liver enzymes and the 17 cytokines. The R-value of each comparison was reflected by the color scale of the heatmap. (B) Spearman correlation of absolute CD4+ T cell counts had an inverse correlation with HIV plasma viral load. The exact R- and p-values were calculated. (C) Spearman correlation between innate cytokines, monocyte-derived cytokines, Th1, Th2, Treg, and Th17 cytokines and enumeration of CD4+ T cell counts post-HAART in HIV/HPgV seronegative and seropositive individuals. p-Values <0.05 are considered significant in all tests; *p < 0.05, **p < 0.01. ALP, alkaline phosphatase; GGT, gamma-glutamyl transferase; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic-pyruvic transaminase.