Effects of Pegylated Interferon Alpha and Ribavirin (pegIFN-α/RBV) Therapeutic Approach on Regulatory T Cells in HCV-Monoinfected and HCV/HIV-Coinfected Patients

Abstract

Approximately 25% of HIV-infected patients are co-infected with HCV. Notably, the burden of HCV infection (e.g., viral persistence, viral load, or HCV-related liver symptoms) is more pronounced in the presence of HIV co-infection. However, to date, the underlying immune mechanisms accounting for accelerated disease progression in HIV/HCV-coinfected individuals have not been described in sufficient detail. We hypothesized that regulatory T cells (Treg) bearing potent immunosuppressive capacities could not only play a substantial role in the pathogenesis of HCV/HIV coinfection but also modulate the response to the standard anti-viral therapy.

Materials and methods: To this end, we studied alterations in frequencies of Treg cells in correlation with other Treg-related and virus-related parameters in both HCV and HCV/HIV-infected patients subjected to standard pegIFN-α/RBV therapy.

Results: Notably, we found that pegIFN-α/RBV therapy significantly increased levels of Treg cells in HCV-infected but not in HIV/HCV-coinfected individuals. Furthermore, HIV/HCV-coinfection was demonstrated to inhibit expansion of regulatory T cells during anti-viral treatment; thus, it might probably be responsible for viral persistence and HCV-related liver damage.

Conclusions: Therapy with pegIFN-α/RBV demonstrated a significant effect on regulatory T cells in the course of HIV and/or HCV infection indicating a crucial role in the anti-viral immune response.

Keywords: HCV; HIV; HIV/HCV-coinfection; pegIFN-α/RBV; regulatory T cells.

Figure 1

Frequencies of regulatory T cells in HCV-infected (left column) and HCV/HIV-coinfected (right column) patients in the course of anti-viral therapy. Data presenting the effects of therapy and differences between studied groups in the course of treatment in relation to healthy control subjects. Treg-related parameters included: Foxp3-positive cells within CD4⁺ (a) and CD4⁺CD25⁺CD127⁻ lymphocytes (b), frequency of CD25⁺CD127⁻Foxp3⁺ (c) and CD25+CD127- (d) in pool of CD4⁺ T cells.

Figure 2

Anti-viral treatment effects on regulatory T cells absolute numbers in HCV-infected (left column) and HCV/HIV-coinfected (right column) patients. Data presenting the effects of therapy and differences between studied groups in the course of treatment in relation to healthy control subjects. Treg-related parameters included: CD4⁺Foxp3⁺ (a), CD4⁺CD25⁺CD127⁻Foxp3⁺ (b), CD4⁺CD25⁺CD127⁻ (c), and total CD4⁺ (d) lymphocytes.

Figure 3

Alterations in T cells activation- (CD25) and development-related (CD127) proteins in the course of anti-viral treatment of HCV-infected and HCV/HIV-coinfected patients. Data presenting effects of therapy and differences between studied groups in the course of treatment in relation to healthy control subjects. CD25 activation marker was analyzed as frequency (a) and mean fluorescence intensity (MFI) (b) within CD4⁺ lymphocytes, and similarly, CD127 was demonstrated as frequency of marker-positive cells (c) and MFI (d) in CD4⁺ T cell pool.

Figure 4

HCV virus genotype effects on frequency and absolute numbers of regulatory T cells in HCV-infected and HCV/HIV-coinfected patients. Treg-related parameters analyzed in context of frequencies: Foxp3⁺ in CD4⁺ (a) and CD4⁺CD25⁺CD127⁻ T cells (b), CD25⁺CD127⁻Foxp3⁺ (c) and CD25+CD127- (d) within CD4⁺ T cell pool; and absolute numbers: Foxp3⁺ (e), CD25⁺CD127⁻Foxp3⁺ (f), CD25+CD127- (g) CD4⁺ lymphocytes, and total CD4⁺ cells (h). Significant changes in relation to healthy controls indicated directly above specific group column; additional differences distinguished with lines connecting significantly different groups.

Figure 5

HCV virus genotype-related differences in regulatory T cells frequencies in response to anti-viral therapy in HCV-infected (left column) and HCV/HIV-coinfected patients (right column). Data related to T regs in HCV or HCV/HIV-coinfected patients presented as: Foxp3⁺ in CD4⁺ (a) and CD4⁺CD25⁺CD127⁻ (b) lymphocytes, CD25⁺CD127⁻Foxp3⁺ (c) and CD25+CD127- (d) within CD4⁺ T cell pool. Significant changes in relation to healthy controls indicated directly above specific group column; additional differences distinguished with lines.

Figure 6

HCV virus genotype-related differences in regulatory T cells absolute numbers in response to anti-viral therapy in HCV-infected (left column) and HCV/HIV-coinfected patients (right column). Treg-related parameters in HCV or HCV/HIV-coinfected patients presented as absolute numbers: Foxp3⁺ (a), CD25⁺CD127⁻Foxp3⁺ (b), CD25+CD127- (c) CD4⁺ lymphocytes, and total CD4⁺ cells (d). Significant changes in relation to healthy controls indicated directly above specific group column; additional differences distinguished with lines connecting significantly different groups.