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

被引：102

作者：

Pillai, Satish K. ^{[1
,2
]}

Abdel-Mohsen, Mohamed ^{[1
]}

Guatelli, John ^{[3
]}

Skasko, Mark ^{[3
]}

Monto, Alexander ^{[1
,2
]}

Fujimoto, Katsuya ^{[2
]}

Yukl, Steven ^{[1
,2
]}

Greene, Warner C. ^{[1
,4
]}

Kovari, Helen ^{[5
]}

Rauch, Andri ^{[6
]}

Fellay, Jacques ^{[7
,8
]}

Battegay, Manuel ^{[9
]}

Hirschel, Bernard ^{[10
]}

Witteck, Andrea ^{[11
]}

Bernasconi, Enos ^{[12
]}

Ledergerber, Bruno ^{[5
]}

Guenthard, Huldrych F. ^{[5
]}

Wong, Joseph K. ^{[1
,2
]}

机构：

[1] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[2] San Francisco VA Med Ctr, Dept Med, San Francisco, CA 94121 USA

[3] Univ Calif San Diego, Vet Affairs San Diego Healthcare Syst, Dept Med, La Jolla, CA 92093 USA

[4] Gladstone Inst Virol & Immunol, San Francisco, CA 94158 USA

[5] Univ Zurich, Univ Zurich Hosp, Div Infect Dis & Hosp Epidemiol, CH-8091 Zurich, Switzerland

[6] Univ Bern, Univ Hosp Berne, Div Infect Dis, CH-3010 Bern, Switzerland

[7] Univ Lausanne Hosp, Div Infect Dis, CH-1011 Lausanne, Switzerland

[8] Univ Lausanne Hosp, Inst Microbiol, CH-1011 Lausanne, Switzerland

[9] Univ Basel Hosp, Div Infect Dis, CH-4031 Basel, Switzerland

[10] Univ Hosp Geneva, Div Infect Dis, CH-1211 Geneva, Switzerland

[11] Cantonal Hosp St Gallen, Div Infect Dis, CH-9007 St Gallen, Switzerland

[12] Reg Hosp Lugano, Div Infect Dis, CH-6903 Lugano, Switzerland

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2012年 / 109卷 / 08期

基金：

美国国家卫生研究院; 瑞士国家科学基金会;

关键词：

IMMUNODEFICIENCY-VIRUS TYPE-1; ANTIRETROVIRAL ACTIVITY; REVERSE TRANSCRIPTION; CYTIDINE DEAMINATION; ANTIVIRAL PROTEIN; VIF PROTEIN; T-CELLS; C VIRUS; APOBEC3G; HYPERMUTATION;

D O I：

10.1073/pnas.1111573109

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The antiviral potency of the cytokine IFN-alpha 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-alpha-mediated suppression of HIV-1 replication in vitro. We sought to characterize the as-yet-undefined relationship between IFN-alpha 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-naive individuals before, during, and after pegylated IFN-alpha/ribavirin (IFN-alpha/riba) combination therapy. IFN-alpha/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-alpha/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 rho), and evolution of the HIV-1 accessory protein viral protein U (Vpu) during IFN-alpha/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-alpha in vivo, and warrant investigation into therapeutic strategies that specifically enhance the expression of these intrinsic immune factors in HIV-1-infected individuals.

引用

页码：3035 / 3040

页数：6

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