How Interferon-alfa performs antiviral activity against HIV

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

1. Satish K. Pillai^a,^b,¹,
2. Mohamed Abdel-Mohsen^a,
3. John Guatelli^c,
4. Mark Skasko^c,
5. Alexander Monto^a,^b,
6. Katsuya Fujimoto^b,
7. Steven Yukl^a,^b,
8. Warner C. Greene^a,^d,
9. Helen Kovari^e,
10. Andri Rauch^f,
11. Jacques Fellay^g,
12. Manuel Battegay^h,
13. Bernard Hirschelⁱ,
14. Andrea Witteck^j,
15. Enos Bernasconi^k,
16. Bruno Ledergerber^e,
17. Huldrych F. Günthard^e,²,
18. Joseph K. Wong^a,^b,², and
19. the Swiss HIV Cohort Study³

+Author Affiliations

1. ^aDepartment of Medicine, University of California, San Francisco, CA 94143;
2. ^bDepartment of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121;
3. ^cDepartment of Medicine, Veterans Affairs San Diego Healthcare System, University of California at San Diego, La Jolla, CA 92093;
4. ^dGladstone Institute of Virology and Immunology, San Francisco, CA 94158;
5. ^eDivision of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, CH-8091 Zurich, Switzerland;
6. ^fDivision of Infectious Diseases, University Hospital Berne, University of Berne, CH-3010 Berne, Switzerland;
7. ^gDivision of Infectious Diseases and Institute of Microbiology, University Hospital Lausanne, CH-1011 Lausanne, Switzerland;
8. ^hDivision of Infectious Diseases, University Hospital Basel, CH-4031 Basel, Switzerland;
9. ⁱDivision of Infectious Diseases, University Hospital of Geneva, CH-1211 Geneva, Switzerland;
10. ^jDivision of Infectious Diseases, Cantonal Hospital of St. Gallen, St. Gallen, CH-9007 Switzerland; and
11. ^kDivision of Infectious Diseases, Regional Hospital of Lugano, CH-6903 Lugano, Switzerland

1. Edited by Robert C. Gallo, Institute of Human Virology, University of Maryland, Baltimore, MD, and approved December 14, 2011 (received for review July 27, 2011)

Abstract

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.

http://www.pnas.org/content/early/2012/02/03/1111573109.abstract