APOBEC3G/3F mediates intrinsic resistance of monocyte-derived dendritic cells to HIV-1 infection

Pion, Marjorie; Granelli‐Piperno, Angela; Mangeat, Bastien; Stalder, Romaine; Corrêa, Rafael; Steinman, Ralph M.; Piguet, Vincent

doi:10.1084/jem.20061519

Cited by 119 publications

(91 citation statements)

References 28 publications

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“…It could be due to the possible inhibition of APOBEC3G on viral RNA packaging (50). Furthermore, we and others have identified that APOBEC3G in the resting CD4 cells and myeloid dendritic cells can effectively inhibit the incoming HIV-1 viruses (30,51,52). This inhibition is also unlikely contributed by its cytidine deaminase activity.…”

Section: Discussionmentioning

confidence: 98%

Virion-associated Uracil DNA Glycosylase-2 and Apurinic/Apyrimidinic Endonuclease Are Involved in the Degradation of APOBEC3G-edited Nascent HIV-1 DNA

Yang¹,

Chen²,

Zhang

et al. 2007

Journal of Biological Chemistry

121

119

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Cellular cytidine deaminases APOBEC3 family is a group of potent inhibitors for many exogenous and endogenous retroviruses. It has been demonstrated that they induce G to A hypermutations in the nascent retroviral DNA, resulting from the cytosine (C) to uracil (U) conversions in minus-stranded viral DNA. In this report, we have demonstrated that the result of C to U conversion in minus-stranded DNA of human immunodeficiency virus type 1 (HIV-1) could trigger a degradation of nascent viral DNA mediated by uracil DNA glycosylases-2 (UNG2) and apurinic/apyrimidinic endonuclease (APE). Since antiviral activity of APOBEC3G is partially affected by UNG2 inhibitor Ugi or UNG2-specific short-interfering RNA in virus-producing cells but not target cells, the virion-associated UNG2 most likely mediates this process. Interestingly, as APE-specific short-interfering RNA can also partially inhibit the anti-HIV-1 activity of APOBEC3G in virus-producing cells but not in target cells and APE molecules can be detected within HIV-1 virions, it seems that the required APE is also virion-associated. Furthermore, the in vitro cleavage experiment using uracil-containing single-stranded DNA as a template has demonstrated that the uracil-excising catalytic activity of virion-associated UNG2 can remove dU from the uracil-containing viral DNA and leave an abasic site, which could be further cleaved by virion-associated APE. Based upon our observations, we propose that the degradation of APOBEC3G-edited viral DNA mediated by virion-associated UNG2 and APE during or after reverse transcription could be partially responsible for the potent anti-HIV-1 effect by APOBEC3G in the absence of vif.APOBEC3 is a family of cytidine deaminases that has been identified as the host factor to restrict various retroviruses, endogenous retroviruses, and long interspersed nucleotide element (LINE) elements (1-11). It is closely related to APOBEC1, a cytidine deaminase that causes a specific cytosine to uracil change in the apolipoprotein B mRNA, and to an activationinduced deaminase (AID) enzyme that causes hypermutation of immunoglobulin genes (12). The similarities of the catalytic domains in these proteins strongly suggest that APOBEC3 edits the nucleic acids of various retrotransposons. Among these cytidine deaminases, APOBEC3G is the most extensively studied enzyme. It can be efficiently incorporated into human immunodeficiency virus type 1 (HIV-1) 4 particles and causes extensive cytosine to uracil conversion in the viral minus-stranded DNA during reverse transcription (2, 3, 13). The significant C to U conversion in minus-stranded DNA is apparently correlated with the decreased viral infectivity. Two consequences could occur after the C to U conversion. First, uracil in minusstranded DNA could be excised by recruited uracil DNA glycosylase-2 (UNG2), a host DNA repair enzyme. The resulting abasic site could be further cleaved by apurinic/apyrimidinic endonucleases (APE). The vif-defective viruses generated from the restrictive cells are unable to effe...

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Section: Discussionmentioning

confidence: 98%

Virion-associated Uracil DNA Glycosylase-2 and Apurinic/Apyrimidinic Endonuclease Are Involved in the Degradation of APOBEC3G-edited Nascent HIV-1 DNA

Yang¹,

Chen²,

Zhang

et al. 2007

Journal of Biological Chemistry

121

119

View full text Add to dashboard Cite

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“…This prevents detection of reverse‐transcribed viral DNA and activation of interferon responses (Gao et al , 2013; Bridgeman et al , 2015; Gentili et al , 2015). Other factors contributing to HIV‐1 escape in DCs have been described and include TREX1, an exonuclease that degrades reverse‐transcribed HIV DNA in the cytoplasm (Yan et al , 2010), and APOBEC3G/3F (A3G/3F) whose knockdown enhances HIV‐1 infection of DCs associated with G‐to‐A hypermutation of the HIV genome (Pion et al , 2006). These observations explain how HIV‐1 avoids innate sensing during uptake into DCs and in the cytosol.…”

Section: Introductionmentioning

confidence: 99%

Snapin promotes HIV ‐1 transmission from dendritic cells by dampening TLR 8 signaling

et al. 2017

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HIV‐1 traffics through dendritic cells (DCs) en route to establishing a productive infection in T lymphocytes but fails to induce an innate immune response. Within DC endosomes, HIV‐1 somehow evades detection by the pattern‐recognition receptor (PRR) Toll‐like receptor 8 (TLR8). Using a phosphoproteomic approach, we identified a robust and diverse signaling cascade triggered by HIV‐1 upon entry into human DCs. A secondary siRNA screen of the identified signaling factors revealed several new mediators of HIV‐1 trans‐infection of CD4+ T cells in DCs, including the dynein motor protein Snapin. Inhibition of Snapin enhanced localization of HIV‐1 with TLR8+ early endosomes, triggered a pro‐inflammatory response, and inhibited trans‐infection of CD4+ T cells. Snapin inhibited TLR8 signaling in the absence of HIV‐1 and is a general regulator of endosomal maturation. Thus, we identify a new mechanism of innate immune sensing by TLR8 in DCs, which is exploited by HIV‐1 to promote transmission.

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“…Decreased A3G expression and susceptibility to HIV-1 occurs during differentiation of human monocytes to monocyte-derived macrophages (13). Conversely, increased A3G expression with enhanced resistance to HIV-1 occurs during dendritic cell maturation (14). Finally, decreased levels of A3G have been noted in the CD4 ϩ T helper 2 (Th2) subset, compared with T helper 1 (Th1) cells (15).…”

mentioning

confidence: 96%

NFAT and IRF Proteins Regulate Transcription of the Anti-HIV Gene, APOBEC3G

Farrow

Kim

Wolinsky

et al. 2011

Journal of Biological Chemistry

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The human cytidine deaminase APOBEC3G (A3G) is an innate restriction factor that inhibits human immunodeficiency virus, type 1 (HIV-1) replication. Regulation of A3G gene expression plays an important role in this suppression. Currently, an understanding of the mechanism of this gene regulation is largely unknown. Here, we have identified and characterized a TATA-less core promoter with an NFAT/ IRF-4 composite binding site that confers cell type-specific transcriptional regulation. We found that A3G expression is critically dependent on NFATc1/NFATc2 and IRF-4. When either NFATc1 or NFATc2 and IRF-4 were co-expressed, A3G promoter activity was observed in cells that normally lack A3G expression and expression was not detected in the presence of the individual factors. This induced A3G expression allowed normally permissive CEMss cells to adopt a nonpermissive state, able to resist an HIV-1⌬vif challenge. This represents the first reporting of manipulating the restrictive state of a cell type via gene regulation. Identification of NFAT and IRF family members as critical regulators of A3G expression offers important insight into the transcriptional control mechanisms that regulate innate immune responses and identifies specific targets for therapeutic intervention aimed at effectively boosting our natural immunity, in the form of a host defensive factor, against HIV-1.Human A3G is an innate immune resistance factor for a broad range of retroviruses. The gene is expressed in hematopoietic cell populations, lymphoid tissues, and selected established T cell lines (1). The A3G protein restricts human immunodeficiency virus, type 1 (HIV-1) 2 infection by accessing the budding virion and disrupting the reverse transcription of HIV-1 RNA in target cells. The post-entry block impairs initiation (2), inhibits transcript elongation (3), and induces Gto-A hypermutation in the nascent viral cDNA through cytidine deamination (4 -7). HIV-1 Vif potently counteracts this restriction in the producer cell by targeting A3G to the proteasome, thereby preventing incorporation of A3G into the virus particle (8 -11). The mechanism for producer cell mediated A3G restriction and HIV-1 Vif counteraction have been extensively studied and characterized (12) and the Vif:A3G regulatory circuit is one of the most interesting examples of how cellular restriction factors participate in the exertion of a powerful intracellular defense mechanism.A3G mRNA and protein levels vary across both developmental and differentiation transitions, and these differences influence the restrictive capacity of the particular cell type. Decreased A3G expression and susceptibility to HIV-1 occurs during differentiation of human monocytes to monocyte-derived macrophages (13). Conversely, increased A3G expression with enhanced resistance to HIV-1 occurs during dendritic cell maturation (14). Finally, decreased levels of A3G have been noted in the CD4 ϩ T helper 2 (Th2) subset, compared with T helper 1 (Th1) cells (15). Taken together, these observations suggest that ...

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APOBEC3G/3F mediates intrinsic resistance of monocyte-derived dendritic cells to HIV-1 infection

Cited by 119 publications

References 28 publications

Virion-associated Uracil DNA Glycosylase-2 and Apurinic/Apyrimidinic Endonuclease Are Involved in the Degradation of APOBEC3G-edited Nascent HIV-1 DNA

Virion-associated Uracil DNA Glycosylase-2 and Apurinic/Apyrimidinic Endonuclease Are Involved in the Degradation of APOBEC3G-edited Nascent HIV-1 DNA

Snapin promotes HIV ‐1 transmission from dendritic cells by dampening TLR 8 signaling

NFAT and IRF Proteins Regulate Transcription of the Anti-HIV Gene, APOBEC3G

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