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

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; Swiss HIV Cohort Study, (2012). Role of retroviral restriction factors in the interferon-α-mediated suppression of HIV-1 in vivo. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 109(8), pp. 3035-40. Washington, D.C.: National Academy of Sciences NAS 10.1073/pnas.1111573109

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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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Infectiology
UniBE Contributor:	Rauch, Andri
ISSN:	0027-8424
Publisher:	National Academy of Sciences NAS
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:37
Last Modified:	05 Dec 2022 14:11
Publisher DOI:	10.1073/pnas.1111573109
PubMed ID:	22315404
Web of Science ID:	000300495100073
URI:	https://boris.unibe.ch/id/eprint/14857 (FactScience: 221993)