Role of retroviral restriction factors in the interferon-α–mediated suppression of HIV-1 in vivo

Satish K. Pillai, Mohamed Abdel-Mohsen, John Guatelli, Mark Skasko, Alexander Monto, Katsuya Fujimoto, Steven Yukl, Warner C. Greene, Helen Kovari, Andri Rauch, Jacques Fellay, Manuel Battegay, Bernard Hirschel, Andrea Witteck, Enos Bernasconi, Bruno Ledergerber, Huldrych F. Günthard, Joseph K. Wong, J Barth, M Battegay, E Bernasconi, J Böni, HC Bucher, C Burton-Jeangros, A Calmy, M Cavassini, C Cellerai, M Egger, L Elzi, J Fehr, J Fellay, M Flepp, P Francioli, H Furrer, CA Fux, M Gorgievski, H Günthard, D Haerry, B Hasse, HH Hirsch, B Hirschel, I Hösli, C Kahlert, L Kaiser, O Keiser, C Kind, T Klimkait, H Kovari, B Ledergerber, G Martinetti, B Martinez de Tejada, K Metzner, N Müller, D Nadal, G Pantaleo, A Rauch, S Regenass, M Rickenbach, C Rudin, P Schmid, D Schultze, F Schöni-Affolter, J Schüpbach, R Speck, P Taffé, P Tarr, A Telenti, A Trkola, P Vernazza, R Weber, S Yerly

The antiviral potency of the cytokine IFN-α has been long appreciated but remains poorly understood. A number of studies have suggested that induction of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 (APOBEC3) and bone marrow stromal cell antigen 2 (BST-2/tetherin/CD317) retroviral restriction factors underlies the IFN-α-mediated suppression of HIV-1 replication in vitro. We sought to characterize the as-yet-undefined relationship between IFN-α treatment, retroviral restriction factors, and HIV-1 in vivo. APOBEC3G, APOBEC3F, and BST-2 expression levels were measured in HIV/hepatitis C virus (HCV)-coinfected, antiretroviral therapy-naïve individuals before, during, and after pegylated IFN-α/ribavirin (IFN-α/riba) combination therapy. IFN-α/riba therapy decreased HIV-1 viral load by -0.921 (±0.858) log(10) copies/mL in HIV/HCV-coinfected patients. APOBEC3G/3F and BST-2 mRNA expression was significantly elevated during IFN-α/riba treatment in patient-derived CD4+ T cells (P < 0.04 and P < 0.008, paired Wilcoxon), and extent of BST-2 induction was correlated with reduction in HIV-1 viral load during treatment (P < 0.05, Pearson's r). APOBEC3 induction during treatment was correlated with degree of viral hypermutation (P < 0.03, Spearman's ρ), and evolution of the HIV-1 accessory protein viral protein U (Vpu) during IFN-α/riba treatment was suggestive of increased BST-2-mediated selection pressure. These data suggest that host restriction factors play a critical role in the antiretroviral capacity of IFN-α in vivo, and warrant investigation into therapeutic strategies that specifically enhance the expression of these intrinsic immune factors in HIV-1-infected individuals.