Differential Specificity of Interferon-alpha Inducible Gene Expression in Association with Human Immunodeficiency Virus and Hepatitis C Virus Levels and Declines in vivo

Abstract

Objective This study was aimed to correlate in vivo interferon (IFN) inducible gene (IFIG) expression and IFIG induction with viral-load (VL) and VL-kinetics of Human-Immunodeficiency-Virus (HIV) or Hepatitis-C-Virus (HCV) in HIV-positive patients treated with pegylated IFN-alpha-2a (PegIFNα). Methods HIV mono-infected patients (N=8) and HIV/HCV co-infected patients (N=23, without HIV-viremia) were treated with PegIFNα (180 μg/week) for 12 and 48 weeks, respectively. Blood sampling for monitoring IFIG expression occurred at day_0 and week_3, _6 and _12 for HIV mono-infected patients vs. only at day_0 and week_48 for HIV/HCV co-infected subjects. IFIG expression (N=20) was measured in peripheral blood mononuclear cells by bDNA-assay. VL levels/changes in plasma were analyzed for correlation with IFIG expression/induction at/between selected time points. Overall, P<0.05 was considered significant. Results None of the 20 IFIG expression profiles at day_0 correlated significantly with HIV-VL at day_0. Expression at day_0 of 3 IFIG (APOBEC3G/OAS1/OAS2) correlated significantly (r>+0.42/P<0.05) with HCV-VL at day_0. The strongest antiviral effect [measured as median viral decline per week: ΔVL/week (log10)] occurred in common against HIV and HCV between day_0 and week_3 during 12 weeks of continuous PegIFNα treatment in both cohorts. Expression at day_0 of 1 IFIG (APOBEC3A) correlated significantly (r<−0.71/P<0.05) with HIV-ΔVL/week (log10) from day_0 to week_3. No significance was reached in correlations between expression values of 20 IFIG at day_0 and HCV-ΔVL/week (log10) from day_0 to week_3. No significant correlation was detected between IFIG expression changes (ΔIFIG=induction) from day_0 to week_3 and HIV-ΔVL/week (log10) from day_0 to week_3. Interestingly, induction of 1 IFIG (ΔISG20) from day_0 to week_48 was significantly associated (P<0.05) with permanent HCV clearance. Conclusion This study demonstrates the differential specificity of PegIFNα mediated molecular actions by dissecting the kinetics of IFIG expression and induction, suggesting multiple, possibly non-overlapping mechanisms for antiviral effects against HCV and HIV.

CMPK2 and BCL-G are associated with type 1 interferon–induced HIV restriction in humans

“…We noted that the baseline abundance of ISGs before IFN-2b, as quantified by the RNA-seq reads per gene (fragments per kilobase of transcript per million mapped reads; fig. S7), was not associated with baseline plasma HIV RNA, similar to the findings reported previously with a more restricted set of ISGs (5). We also found that a summary measure of ISG induction (quantified as the mean fold change in expression of all 99 ISGs) in each participant was only marginally associated with plasma HIV RNA decline (P = 0.08, R = −0.41; fig.…”

“…Interferon-2b (IFN-2b), a quintessential type 1 interferon (IFN), has been used to treat chronic viral infections and has been tested in clinical trials against HIV. HIV-infected individuals treated with IFN experience a decline in the abundance of plasma viral RNA (3)(4)(5) and the number of cells harboring viral genomes (6). Sandler and colleagues, among others, have provided firm evidence that simian immunodeficiency virus (SIV) control by type 1 IFN requires induction of ISGs: They recently demonstrated that inhibition of type 1 IFN signaling in rhesus macaques reduced ISG induction and enhanced SIV replication and progression to AIDS (7)(8)(9).…”

APOBEC3G/3A Expression in Human Immunodeficiency Virus Type 1-Infected Individuals Following Initiation of Antiretroviral Therapy Containing Cenicriviroc or Efavirenz

“…A3A transcripts were shown to be downregulated after initiation of antiretroviral therapy in whole blood samples from 10 Ugandans with AIDS ( 40 ). In addition, A3A baseline expression in PBMCs from HIV-1-infected patients was found to significantly correlate with viral load decline observed following 3 weeks of treatment with pegylated IFN-α-2a ( 41 ). Although in the patients’ cohort analyzed in this study A3A levels do not correlate with either viral load or CD4 + /CD8 + cell counts and ratios, an inverse correlation was found between A3A expression and sCD14 levels.…”