Increased Peripheral Blood Leukocyte Subsets with Regulatory Phenotype in Clinically Stable Long-Term HIV-Infected Hemophilia Patients on HAART May Be Beneficial and Contribute to a Decrease in Autoimmunity

Abstract

After initiation of highly-active antiretroviral therapy (HAART), long-term HIV-infected hemophilia patients have been shown to lose autoantibodies against CD4⁺ peripheral blood leukocytes (PBL), suggesting that HAART induces autoimmunity-blocking mechanisms. We compared cytokine levels and subpopulations of lymphocytes and dendritic cells (DC) in the blood of 40 long-term HIV⁺ patients with those of 13 long-term HIV^– hemophilia patients; 23 HIV⁺ patients had a detectable retroviral load. Cell subsets were determined using flow cytometry and cytokine levels were measured using ELISA. HIV⁺ patients showed higher proportions of DC subpopulations with immunostimulatory phenotypes (p < 0.01), CD8⁺ PBL (p < 0.001), and IL-2 (p < 0.001) and sIL-2R plasma levels (p = 0.002) than HIV^– patients. They also exhibited increased proportions of T PBL with immunosuppressive phenotypes such as CD3⁺CD4⁺CD25⁺Foxp3⁺ (p = 0.001), and CD3⁺CD8⁺CD28^–Foxp3⁺ PBL (p < 0.001), and a decreased IL-7R expression on CD3⁺CD8⁺ PBL (p = 0.001) compared to HIV^– patients. Frequencies of CD3⁺CD4⁺CD25⁺ PBL producing IL-2, IL-4, IL-10, IL-12, and/or IFN-γ, and of CD3⁺CD4⁺CD28^– PBL secreting IL-2 and/or IL-4 were lower in HIV⁺ than in HIV^– patients (p ≤ 0.02). Proportions of CD4⁺ PBL coated with IgG, IgM, and C3d were similar in HIV⁺ and HIV^– patients (p = n.s.). However, the proportion of CD4⁺gp120⁺ PBL was higher in HIV⁺ patients (p = 0.002), and associated with low CD3⁺CD4⁺CD25⁺Foxp3⁺ PBL (p = 0.012). We conclude that long-term HIV-infected hemophilia patients on HAART show an adaptive immune response, presumably against HIV, in the presence of upregulated immunosuppressive T PBL, downregulated cytokine-producing CD4⁺ PBL, and downregulated IL-7R expression on CD8⁺ PBL. Increased immunoregulatory T PBL might decrease autoimmunity, thereby contributing to immunological reconstitution and stabilization of long-term HIV-infected hemophilia patients on HAART.