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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 8; pp. 3035 - 3040
• Main Authors: Pillai, Satish K, Abdel-Mohsen, Mohamed, Guatelli, John, Skasko, Mark, Monto, Alexander, Fujimoto, Katsuya, Yukl, Steven, Greene, Warner C, Kovari, Helen, Rauch, Andri, Fellay, Jacques, Battegay, Manuel, Hirschel, Bernard, Witteck, Andrea, Bernasconi, Enos, Ledergerber, Bruno, Günthard, Huldrych F, Wong, Joseph K
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 21-02-2012; National Acad Sciences
• Subjects: alpha -Interferon; Amino Acid Sequence; antigens; Antigens, CD - genetics; Antigens, CD - metabolism; Antiretrovirals; Antiviral agents; antiviral properties; Antivirals; APOBEC-3G Deaminase; Apolipoprotein B; Biological Sciences; Bone marrow; bone marrow cells; CD4 antigen; CD4-positive T-lymphocytes; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - virology; Cytidine Deaminase - genetics; Cytidine Deaminase - metabolism; Cytokines; Cytosine Deaminase - genetics; Cytosine Deaminase - metabolism; Data processing; drug therapy; Enzymes; Evolution; Evolution, Molecular; Gene expression; Genetic mutation; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; Hepatitis C virus; HIV; HIV 1; HIV infections; HIV-1 - drug effects; Human immunodeficiency virus 1; Human Immunodeficiency Virus Proteins - chemistry; Human Immunodeficiency Virus Proteins - metabolism; Humans; Infections; interferon-alpha; Interferon-alpha - pharmacology; Lymphocytes T; Messenger RNA; Molecular Sequence Data; Mutation - genetics; Replication; Ribavirin; Ribavirin - pharmacology; RNA editing; stromal cells; T lymphocytes; Viral load; viral proteins; Viral Regulatory and Accessory Proteins - chemistry; Viral Regulatory and Accessory Proteins - metabolism; Viremia - immunology; Viremia - virology; virus replication; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1111573109

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) 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 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.