HCV viraemia associates with NK cell activation and dysfunction in antiretroviral therapy‐treated HIV/HCV‐co‐infected subjects

Abstract

The impact of Hepatitis C virus (HCV) RNA levels on immune status in chronically HCV mono-infected when compared to HIV/HCV co-infected on antiretroviral therapy (ART) remains poorly understood. A total of 78 African American subjects HCV viremic/naïve to HCV treatment (33 HCV genotype 1 mono-infected, 45 HCV genotype 1/HIV co-infected on ART) were studied. Clinical and liver enzymes measurements were performed. Whole blood was analyzed for immune subset changes by flow-cytometry. Peripheral blood mononuclear cells (PBMC) were used for same-day constitutive and in vitro Interferon (IFN)-α-induced Signal Transducer and Activator of Transcription (STAT) phosphorylation, K562 target cell lysis and K562 target cell recognition-mediated IFN-γ production. Statistical analysis was done using R (2.5.1) or JMP Pro 11. While both groups did not differ in the level of liver enzymes, HIV/HCV had higher T cell activation/exhaustion, and constitutive STAT-1 phosphorylation compared to HCV. In contrast, CD4+FoxP3+CD25+ frequency, IFN-αR expression on NK cells, as well as constitutive and IFN-α-induced direct cytotoxicity were lower in HIV/HCV. Linear regression models further supported these results. Finally, increase in HCV viral load (vl) and CD4+ T cell count had an opposite effect between the two groups on NK cell activity, and T cell activation respectively. HCV viraemia in antiretroviral -treated HIV/HCV co-infection was associated with greater immune activation/exhaustion and NK dysfunction than HCV viral load alone in HCV mono-infection. The more pronounced immune modulation noted in antiretroviral treated HIV co-infected / untreated HCV viremic subjects may impact HCV disease progression and/or response to immunotherapy.

Gene expression profiling informs HPV cervical histopathology but not recurrence/relapse after LEEP in ART-suppressed HIV+HPV+ women

“…HR HPV infection of ART-suppressed HIV + women. The presence of sustained systemic immune activation in the blood of women coinfected with HR HPV and HIV aligns with data showing increased immune activation in hepatitis C virus/HIV coinfected subjects on ART as compared with hepatitis C virus mono-infected subjects(68)(69)(70)(71)(72). We now expand on these data by showing an association between tissue gene expression and cervical histopathology within HR HPV types.…”

The impact of antiretroviral therapy on iron homeostasis and inflammation markers in HIV-infected patients with mild anemia

“…Most recently, Rosado-Sanchez et al [ 28 ] observed that high levels of IL-6, CRP, high CD4 + cell turnover and regulatory T cell (Treg) frequency are already present prior to initiation of cART in HIV-infected patients with poorer CD4 + cell recovery, suggesting a role of inflammation on CD4 + cell homeostasis. In HIV-infected patients the chronic exposure to other antigens or pathogens, like cytomegalovirus (CMV) or HCV, may also contribute to persistent inflammation or immune activation [ 29 – 31 ] and clinical events [ 32 , 33 ]. In cART-treated HIV-infection with minimal CD4 + cell defects, HCV seems not to be associated with cellular immune activation, but it may rather contribute to immune exhaustion [ 30 ].…”

NK Response Correlates with HIV Decrease in Pegylated IFN-α2a–Treated Antiretroviral Therapy–Suppressed Subjects

“…Immunophenotypic characterization of NK cells, dendritic cells (DC), and T cell subsets was performed by same-day whole blood five-color staining as previously described (28,29) using the following combinations of directly fluorochrome-conjugated anti-human cell-surface mAbs: 1) CD56-FITC, CD3-PerCP-Cy5.5, CD94-allophycocyanin, and CD16-allophycocyanin-Cy7; 2) CD56-FITC, CD25-PE, CD3-PerCP-Cy5.5, HLA-DR-allophycocyanin, and CD16-allophycocyanin-Cy7; 3) CD158a (killer cell Ig-like receptor, two Ig domains and long cytoplasmic tail 1 [KIR2DL1]-FITC, CD158b (KIR2DL, two domains, long cytoplasmic tail 2/3 [KIR2DL2/DL3]-PE, CD3-PerCP-Cy5.5, CD94-allophycocyanin, and CD56-allophycocyanin-Cy7; 4) CD1c (blood DC Ag 1 [BDCA1]-FITC, CD303 (BDCA2)-PE, CD304 (BDCA4)-PE, CD11c-PerCP-Cy5.5, CD197 (CCR type 7 [CCR7])-allophycocyanin, and CD19-allophycocyanin-Cy7; 5) CD95-FITC, CD25-PE, CD3-PerCP-Cy5.5, CD38-allophycocyanin, and CD4-allophycocyanin-Cy7; and 6) CD3-PerCP-Cy5.5, HLA-DR-allophycocyanin, and CD4-allophycocyanin-Cy7. Isotypes used included IgG1k-FITC, IgG1k-PE, IgG1k-PerCP-Cy5.5, IgG1k-allophycocyanin, and IgG1k-allophycocyanin-Cy7.…”

“…This staining allowed for the assessment of markers of CD107a (marker of degranulation) and NKp46 (activating receptor) on NK cell subsets (identified as Lin3 2 CD56 bright and Lin3 2 CD56 dim with or without CD16, with Lin3 consisting of CD3, CD14, CD19, and CD20). 51 Cr release assay for NK cytotoxicity NK function was assessed measuring constitutive and IFN-a (5000 U/ml)induced NK cell-mediated cytotoxicity by standard 51 Cr release assay, as previously described, using fresh PBMC preparations as effector cells against the tumor-derived erythroblastoid cell line K562 (29,33). Briefly, viable fresh PBMC preparations from whole blood (effector cells) were treated for 18 h at 37˚C with medium alone or IFN-a (5000 U/ml; PBL).…”