Expression of regeneration and tolerance factor correlates directly with human immunodeficiency virus infection and inversely with hepatitis C virus infection

Abstract

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause two of the most prevalent debilitating viral infections. HIV appears to induce a skewing toward a Th2 response, while in HCV infection a Th1 response appears to dominate. Regeneration and tolerance factor (RTF) may participate in driving or sustaining a Th2 cytokine response. The expression of RTF on CD3(+) T cells of HIV-seropositive (HIV(+)) individuals is increased. The purpose of this study was to compare the expression of RTF during HIV infections with that during HCV infections. Three-color flow-cytometric analysis of peripheral blood collected from HIV(+) HCV-seropositive (HCV(+)), HIV- and HCV-seropositive (HIV(+) HCV(+)), and HIV- and HCV-seronegative (HIV(-) HCV(-)) individuals was performed. Levels of RTF expression on T-lymphocyte subsets from these groups were compared, as were levels of RTF expression on activated T cells expressing CD38 and HLA-DR, to determine the relationship of RTF expression to these infections. We demonstrated that the expression of RTF on surfaces of T cells from HIV(+) individuals is upregulated and that its expression on T cells from HCV(+) individuals is downregulated. A twofold increase in the mean channel fluorescence of RTF on CD3(+) T cells was seen in both HIV(+) and HIV(+) HCV(+) individuals compared to HIV(-) HCV(-) individuals. HCV(+) individuals had lower levels of RTF expression than HIV(-) HCV(-) individuals (P < 0.005 for CD4(+); P < 0.0005 for CD8(+)). In terms of percentages of T cells expressing RTF, the groups were ranked as follows: HIV(+) > HIV(+) HCV(+) > HIV(-) HCV(-) > HCV(+). The results indicate that RTF expression correlates with HIV-associated immune activation and may be associated with Th2-type responses.

FIG. 1

Flow-cytometric analysis of RTF expression on CD3⁺ T cells from peripheral blood of HIV⁺, HIV⁺ HCV⁺, and HCV⁺ individuals, expressed as MCF ratios (A) and as percentage of cells positive for RTF (B). (A) ∗, a P value of <0.001 indicates that the difference between the ratio for that group is statistically significantly different from that of the HCV⁺ group. (B) ∗, significance is defined as a P value of <0.05, versus the HIV⁻ HCV⁻ group value. Means and standard errors (bars) are shown.

FIG. 2

Flow-cytometric analysis of RTF expression on CD4⁺ and CD8⁺ T cells from HIV⁺, HIV⁺ HCV⁺, HCV⁺, and HIV⁻ HCV⁻ individuals, expressed as MCF of RTF⁺ cells (A) and as percentage of cells expressing RTF (B). Means and standard errors are shown. ∗, significance is defined as a P value of <0.05 (versus HIV⁻ HCV⁻ group value).

FIG. 3

Flow-cytometric dot plots of CD4⁺ T cells (A, C, E, and G) and CD8⁺ T cells (B, D, F, and H) from an HIV⁺ (A and B), HIV⁺ HCV⁺ (C and D), HIV⁻ HCV⁻ (E and F), or HCV⁺ (G and H) individual. A gate was drawn on the CD4⁺ or CD8⁺ cells, and the percentage of double-positive (RTF⁺ CD4⁺ or RTF⁺ CD8⁺) cells was determined by measuring FITC and PC5 fluorescence. Percentages indicate the proportions of cells expressing RTF.