Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells

Chiu, Ya‐Lin; Soros, Vanessa B.; Kreisberg, Jason F.; Stopak, Kim; Yonemoto, Wes; Greene, Warner C.

doi:10.1038/nature03493

Cited by 406 publications

(518 citation statements)

References 30 publications

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“…The GFP-labeled virions infecting CCR5 ϩ HEK 293 cells are independent of CD4 and CCR5 expression due to the presence of a VSV envelope, so inhibition of the viral infection is most likely to be due to the intracellular A3G generated by stimulation with HSP70. Furthermore, the pseudo virus features only a single round of infection, which suggests that the A3G-inhibitory effect occurs during the early stages of infection, as observed recently with the low molecular mass (LMM) form of A3G (8). Interestingly, there is evidence that LMM A3G may be resistant to the actions of Vif, FIGURE 5.…”

Section: Discussionmentioning

confidence: 66%

“…thus making it more desirable as an anti-HIV agent than its nonVif-resistant high molecular mass A3G counterpart (8). Whether HSP70 up-regulates only the LMM or both forms of A3G requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…This is an enzyme with a molecular mass of 46 kDa, which is packaged into retroviral virions and deaminates viral cytidine to uridine, rendering them nonfunctional and inhibiting viral replication. Recently, A3G has also been found to inhibit HIV by an additional mechanism, possibly at or before reverse-transcription (RT) stage of the viral RNA (8). This innate mechanism of resistance to retroviral infection is counteracted by the HIV-1 viral infectivity factor (Vif), which protects the virus by preventing incorporation of A3G into virions and by rapidly inducing its ubiquitination and proteasomal degradation (9 -12).…”

Section: Stimulation Of Cell Surface Ccr5 and Cd40 Molecules By Theirmentioning

confidence: 99%

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Stimulation of Cell Surface CCR5 and CD40 Molecules by Their Ligands or by HSP70 Up-Regulates APOBEC3G Expression in CD4+ T Cells and Dendritic Cells

Pido-Lopez

Whittall

Wang

et al. 2007

The Journal of Immunology

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Apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like-3G (A3G) is an intracellular innate antiviral factor that deaminates retroviral cytidine to uridine. In an attempt to harness the anti-HIV effect of A3G, we searched for an agent that would up-regulate A3G and identify the receptors involved. Stimulation of cell surface CCR5 with CCL3 and CD40 with CD40L or both molecules with microbial 70-kDa heat shock protein (HSP)70 up-regulated A3G mRNA and protein expression in human CD4+ T cells and monocyte-derived dendritic cells (DC), demonstrated by real-time PCR and Western blots, respectively. The specificity of CCR5 and CD40 stimulation was established by inhibition with TAK 779 and mAb to CD40, as well as using human embryonic kidney 293 cells transfected with CCR5 and CD40, respectively. A dose-dependent increase of A3G in CCL3- or HSP70-stimulated CD4+ T cells was associated with inhibition in HIV-1 infectivity. To differentiate between the inhibitory effect of HSP70-induced CCR5 binding and that of A3G, GFP-labeled pseudovirions were used to infect human embryonic kidney 293 cells, which showed inhibition of pseudovirion uptake, consistent with A3G being responsible for the inhibitory effect. Ligation of cell surface CCR5 receptors by CCL3 or CD40 by CD40L activated the ERK1/2 and p38 MAPK signaling pathways that induced A3G mRNA expression and production of the A3G protein. These in vitro results were corroborated by in vivo studies in rhesus macaques in which A3G was significantly up-regulated following immunization with SIVgp120 and p27 linked to HSP70. This novel preventive approach may in addition to adaptive immunity use the intracellular innate antiviral effect of A3G.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Stimulation Of Cell Surface Ccr5 and Cd40 Molecules By Theirmentioning

confidence: 99%

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Stimulation of Cell Surface CCR5 and CD40 Molecules by Their Ligands or by HSP70 Up-Regulates APOBEC3G Expression in CD4+ T Cells and Dendritic Cells

Pido-Lopez

Whittall

Wang

et al. 2007

The Journal of Immunology

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“…[20][21][22][23] Recent evidence suggests that some of the HIV restriction exerted by A3G may be independent of its cytidine deaminase activity. [24][25][26] G-to-A hypermutated HBV genomes have been detected in the plasma of HBV-infected patients, suggesting that APOBEC3 editing enzymes have edited the minus strand cDNA during HBV replication. [27][28][29] In hepatoma cells, transfection of A3B, A3C, A3F, or A3G induced extensive hypermutations in a minor fraction (approximately 10 Ϫ3 ) of HBV genomes that was detected by a novel polymerase chain reaction technique (3D-PCR) designed to selectively amplify AT-hypermutated sequences.…”

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confidence: 99%

Interferon‐inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication†

et al. 2006

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Hypermutations in hepatitis B virus (HBV) DNA by APOBEC3 cytidine deaminases have been detected in vitro and in vivo, and APOBEC3G (A3G) and APOBEC3F (A3F) have been shown to inhibit the replication of HBV in vitro, but the presumably low or even absent hepatic expression of these enzymes has raised the question as to their physiological impact on HBV replication. We show that normal human liver expresses the mRNAs of APOBEC3B (A3B), APOBEC3C (A3C), A3F, and A3G. In primary human hepatocytes, interferon alpha (IFN-␣) stimulated the expression of these cytidine deaminases up to 14-fold, and the mRNAs of A3G, A3F, and A3B reached expression levels of 10%, 3%, and 3%, respectively, relative to GAPDH mRNA abundance. On transfection, the full-length protein A3B L inhibited HBV replication in vitro as efficiently as A3G or A3F, whereas the truncated splice variant A3B S and A3C had no effect. A3B L and A3B S were detected predominantly in the nucleus of uninfected cells; however, in HBV-expressing cells both proteins were found also in the cytoplasm and were associated with HBV viral particles, similarly to A3G and A3F. T he hepatitis B virus (HBV) infects more than 350 million people worldwide and is a leading cause of end-stage liver disease and of hepatocellular carcinoma. 1 HBV is non-cytopathic for hepatocytes; however, most newly HBV infected adult patients develop acute hepatitis because of a strong immune response that clears HBV from the liver, whereas approximately 5% of newly HBV-infected adult patients generate insufficient immunity and become chronically infected. 1,2 Administration of interferon alpha (IFN-␣) is a mainstay of therapy for chronically HBV-infected patients. 2 Interferons restrict the replication of HBV by inducing the expression of antiviral proteins that inhibit the formation of replication-competent HBV nucleocapsids, and ultimately can result in the resolution of the chronic HBV infection. 2-7 HBV and other hepadnaviruses replicate their partially double-stranded DNA genome within cytoplasmic core particles by reverse transcription of encapsidated pregenomic RNA and thus are related to retroviruses. 8,9 The cytidine deaminase APOBEC3G (A3G), which is encoded within a cluster of seven related editing enzymes (APOBEC3A-G) on chromosome 22, provides broad innate immunity against exogenous and endogenous retroelements. 10-16 Encapsidated into the retroviral particle A3G deaminates dCs of the retroviral minus strand

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“…Recently it was demonstrated that intracellular apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) has a role in blocking HIV-1 replication in quiescent CD4 ϩ T cells and monocytes (24). In activated CD4 ϩ T cells and monocyte-derived macrophages APOBEC3G is present as a high molecular mass (HMM) inactive ribonucleoprotein complex that correlates with these cells being permissive for HIV-1 replication.…”

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confidence: 99%

The CD16+ Monocyte Subset Is More Permissive to Infection and Preferentially Harbors HIV-1 In Vivo

Ellery

Tippett

Chiu

et al. 2007

The Journal of Immunology

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276

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HIV-1 persists in peripheral blood monocytes in individuals receiving highly active antiretroviral therapy (HAART) with viral suppression, despite these cells being poorly susceptible to infection in vitro. Because very few monocytes harbor HIV-1 in vivo, we considered whether a subset of monocytes might be more permissive to infection. We show that a minor CD16+ monocyte subset preferentially harbors HIV-1 in infected individuals on HAART when compared with the majority of monocytes (CD14highCD16−). We confirmed this by in vitro experiments showing that CD16+ monocytes were more susceptible to CCR5-using strains of HIV-1, a finding that is associated with higher CCR5 expression on these cells. CD16+ monocytes were also more permissive to infection with a vesicular stomatitis virus G protein-pseudotyped reporter strain of HIV-1 than the majority of monocytes, suggesting that they are better able to support HIV-1 replication after entry. Consistent with this observation, high molecular mass complexes of apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G) were observed in CD16+ monocytes that were similar to those observed in highly permissive T cells. In contrast, CD14highCD16− monocytes contained low molecular mass active APOBEC3G, suggesting this is a mechanism of resistance to HIV-1 infection in these cells. Collectively, these data show that CD16+ monocytes are preferentially susceptible to HIV-1 entry, more permissive for replication, and constitute a continuing source of viral persistence during HAART.

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Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells

Cited by 406 publications

References 30 publications

Stimulation of Cell Surface CCR5 and CD40 Molecules by Their Ligands or by HSP70 Up-Regulates APOBEC3G Expression in CD4+ T Cells and Dendritic Cells

Stimulation of Cell Surface CCR5 and CD40 Molecules by Their Ligands or by HSP70 Up-Regulates APOBEC3G Expression in CD4+ T Cells and Dendritic Cells

Interferon‐inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication†

The CD16+ Monocyte Subset Is More Permissive to Infection and Preferentially Harbors HIV-1 In Vivo

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