Role of retroviral restriction factors in the interferon-[alpha]-mediated suppression of HIV-1 in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 8; p. 3035
• Main Authors: Pillai, Satish K, Abdel-Mohsen, Mohamed, Guatelli, John, Skasko, Mark, Monto, Alexander, Fujimoto, Katsuya, Yuki, Steven, Greene, Warner C, Kovari, Helen, Rauch, Andrea, Fellay, Jacques, Battegay, Manuel, Hirschel, Bernard, Witteck, Andrea, Bernasconi, Enos, Ledergerber, Bruno, Günthard, Huldrych F, Wong, Joseph K
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 21.02.2012
• Subjects: Antigens; Antiretroviral drugs; Bone marrow; Hepatitis; HIV; Human immunodeficiency virus; Proteins
• ISSN: 0027-8424; 1091-6490

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-naive 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) log10 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 ...), 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. (ProQuest: ... denotes formulae/symbols omitted.)