Role of retroviral restriction factors in the interferon-α-mediated suppression of HIV-1 in vivo - PubMed (original) (raw)

. 2012 Feb 21;109(8):3035-40.

doi: 10.1073/pnas.1111573109. Epub 2012 Feb 6.

Mohamed Abdel-Mohsen, John Guatelli, Mark Skasko, Alexander Monto, Katsuya Fujimoto, Steven Yukl, Warner C Greene, Helen Kovari, Andri Rauch, Jacques Fellay, Manuel Battegay, Bernard Hirschel, Andrea Witteck, Enos Bernasconi, Bruno Ledergerber, Huldrych F Günthard, Joseph K Wong; Swiss HIV Cohort Study

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

Satish K Pillai et al. Proc Natl Acad Sci U S A. 2012.

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) 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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

IFN-α/riba treatment strongly suppresses HIV-1 viremia. (A) Blood plasma HIV-1 viral load before, during, and after treatment. (B) CD4+ cell counts before, during, and after treatment. (C) Log10 reduction in HIV-1 viral load plotted against percent change in CD4+ lymphocyte count. Reported P values were obtained using a paired Wilcoxon test (A and B) or a Spearman's ρ (C).

Fig. 2.

Fig. 2.

APOBEC3G, APOBEC3F, and BST-2/tetherin are significantly induced in CD4+ T cells during IFN-α/riba treatment. (A) APOBEC3, tetherin/BST2, and IFN-stimulated gene 15 (ISG15) expressions in unfractionated PBMCs (mean expression is plotted, and error bars represent SEM). (B) APOBEC3, tetherin/BST2, and ISG15 expression in isolated CD4+ T cells. The expression of ISG15 was measured as a positive control in these experiments to confirm IFN-α exposure and response during the treatment period. *P < 0.05; **P < 0.005. (C) Relationship between restriction factor induction and ISG15 induction in CD4+ T cells during IFN-α/riba treatment. (D) Relationship between HIV-1 viral load reduction and restriction factor induction in CD4+ T cells during IFN-α/riba treatment.

Fig. 3.

Fig. 3.

APOBEC3-induced HIV-1 hypermutation during IFN-α/riba treatment. (A) Relationship between GG to AG (APOBEC3G dinucleotide context) viral hypermutation level during treatment and APOBEC3G relative mRNA copy number. (B) Relationship between GA to AA (APOBEC3F dinucleotide context) viral hypermutation level during treatment and APOBEC3F relative mRNA copy number. (C) Relative frequency of APOBEC3G- and APOBEC3F-associated mutations (mean values are plotted and error bars represent SEM). (D) Example of treatment-associated viral hypermutation from a single individual. Red tick mark, GG → AG mutation (APOBEC3G pattern); cyan, GA → AA (APOBEC3F pattern); green, GC → AC; magenta, GT → AT; black, all other mutations; yellow, deletion (compared with pretreatment consensus sequence). Shaded sequences in the bottom half of the panel represent pretreatment PBMC-derived HIV-1 DNA clones, and the sequences in the top, unshaded one of the panel represent PBMC-derived HIV-1 DNA clones from the IFN-α/riba treatment period. Sequences span an ∼500-bp region of the env and nef genes, and ∼20 clones per time point per individual were analyzed.

Fig. 4.

Fig. 4.

Evolution of the HIV-1 Vpu protein during IFN-α/riba treatment. (A) Amino acid sequences of HIV-1 Vpu generated from nine individuals before and during IFN-α/riba treatment. Dashes indicate identity to the HXB2 reference sequence. Vpu positions 11 and 61 are shaded. (B) Effects of A11G and S61A treatment-associated Vpu mutations on Vpu-mediated down-regulation of BST-2 surface expression measured by flow cytometry. Shaded histograms represent mock DNA-transfected cells (negative control).

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