Role of retroviral restriction factors in the interferon-α-mediated suppression of HIV-1 in vivo.
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.
Department of Medicine, University of California, San Francisco, CA 94143, USA. satish.pillai@ucsf.edu
Satish K
SK
Pillai
Mohamed
M
Abdel-Mohsen
John
J
Guatelli
Mark
M
Skasko
Alexander
A
Monto
Katsuya
K
Fujimoto
Steven
S
Yukl
Warner C
WC
Greene
Helen
H
Kovari
Andri
A
Rauch
Jacques
J
Fellay
Manuel
M
Battegay
Bernard
B
Hirschel
Andrea
A
Witteck
Enos
E
Bernasconi
Bruno
B
Ledergerber
Huldrych F
HF
Günthard
Joseph K
JK
Wong
D000071480:APOBEC-3G Deaminase; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism*; D019143:Evolution, Molecular; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D054298:Human Immunodeficiency Virus Proteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D012254:Ribavirin / Q000494:pharmacology; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry / Q000378:metabolism; D014766:Viremia / Q000276:immunology / Q000821:virology; D000074010:Bone Marrow Stromal Antigen 2; D000086082:Viroporin Proteins
D000071480:APOBEC-3G Deaminase; D015703:Antigens, CD; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase; D058851:GPI-Linked Proteins; D054298:Human Immunodeficiency Virus Proteins; D016898:Interferon-alpha; D012254:Ribavirin; D054334:Viral Regulatory and Accessory Proteins; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2; C514859:vpu protein, Human immunodeficiency virus 1; D000086082:Viroporin Proteins; C492906:APOBEC3F protein, human; C464924:APOBEC3G protein, human