APOBEC proteins and intrinsic resistance to HIV-1 infection

Malim, Michael H.

doi:10.1098/rstb.2008.0185

Cited by 243 publications

(271 citation statements)

References 138 publications

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“…48 Because A3G is packaged within HIV-1 virions during late events of virus replication, overlapping with NGF effects on HIV-1 transcription and viral production, we analyzed the ability of this neurotrophin to modulate the synthesis of this restriction factor. In fact, NGF diminished the basal levels of A3G content in macrophages.…”

Section: Discussionmentioning

confidence: 99%

The nerve growth factor reduces APOBEC3G synthesis and enhances HIV-1 transcription and replication in human primary macrophages

Souza

Rodrigues²,

Passaes

et al. 2011

Blood

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Macrophages infected with HIV-1 sustain viral replication for long periods of time, functioning as viral reservoirs. Therefore, recognition of factors that maintain macrophage survival and influence HIV-1 replication is critical to understanding the mechanisms that regulate the HIV-1–replicative cycle. Because HIV-1–infected macrophages release the nerve growth factor (NGF), and NGF neutralization reduces viral production, we further analyzed how this molecule affects HIV-1 replication. In the present study, we show that NGF stimulates HIV-1 replication in primary macrophages by signaling through its high-affinity receptor Tropomyosin-related Kinase A (TrKA), and with the involvement of reticular calcium, protein kinase C, extracellular signal-regulated kinase, p38 kinase, and nuclear factor-κB. NGF-induced enhancement of HIV-1 replication occurred during the late events of the HIV-1–replicative cycle, with a concomitant increase in viral transcription and production. In addition, NGF reduced the synthesis of the cellular HIV-1 restriction factor APOBEC3G and also overrode its interferon-γ–induced up-regulation, allowing the production of a well-fitted virus. Because NGF-TrKA signaling is a crucial event for macrophage survival, it is possible that NGF-induced HIV-1 replication plays a role in the maintenance of HIV-1 reservoirs. Our study may contribute to the understanding of the immunopathogenesis of HIV-1 infection and provide insights about approaches aimed at limiting viral replication in HIV-1 reservoirs.

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Section: Discussionmentioning

confidence: 99%

The nerve growth factor reduces APOBEC3G synthesis and enhances HIV-1 transcription and replication in human primary macrophages

Souza

Rodrigues²,

Passaes

et al. 2011

Blood

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“…[1][2][3]. The seven A3 proteins in the human genome share a strong preference for deaminating cytidines that are in a CC or TC context in single-stranded DNA (edited cytidine underlined).…”

Section: A3mentioning

confidence: 99%

Innate Immune Signaling Induces High Levels of TC-specific Deaminase Activity in Primary Monocyte-derived Cells through Expression of APOBEC3A Isoforms

Thielen

McNevin

McElrath

et al. 2010

Journal of Biological Chemistry

105

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In HIV-1-infected individuals, G-to-A hypermutation is found in HIV-1 DNA isolated from peripheral blood mononuclear cells (PBMCs). These mutations are thought to result from editing by one or more host enzymes in the APOBEC3 (A3) family of cytidine deaminases, which act on CC (APOBEC3G) and TC (other A3 proteins) dinucleotide motifs in DNA (edited cytidine underlined). Although many A3 proteins display high levels of deaminase activity in model systems, only low levels of A3 deaminase activity have been found in primary cells examined to date. In contrast, here we report high levels of deaminase activity at TC motifs when whole PBMCs or isolated primary monocyte-derived cells were treated with interferon-␣ (IFN␣) or IFN␣-inducing toll-like receptor ligands. Induction of TC-specific deaminase activity required new transcription and translation and correlated with the appearance of two APOBEC3A (A3A) isoforms. Knockdown of A3A in monocytes with siRNA abolished TC-specific deaminase activity, confirming that A3A isoforms are responsible for all TC-specific deaminase activity observed. Both A3A isoforms appear to be enzymatically active; moreover, our mutational studies raise the possibility that the smaller isoform results from internal translational initiation. In contrast to the high levels of TC-specific activity observed in IFN␣-treated monocytes, CC-specific activity remained low in PBMCs, suggesting that A3G deaminase activity is relatively inhibited, unlike that of A3A. Together, these findings suggest that deaminase activity of A3A isoforms in monocytes and macrophages may play an important role in host defense against viruses. A33 proteins are cytidine deaminases that are capable of inhibiting replication of retroviruses, DNA viruses, and retroelements (reviewed in Refs. 1-3). The seven A3 proteins in the human genome share a strong preference for deaminating cytidines that are in a CC or TC context in single-stranded DNA (edited cytidine underlined). Although APOBEC3G (A3G), the best understood A3 protein, acts preferentially on CC motifs, the six other human A3 proteins display varying degrees of preference for TC motifs (4 -13). Because other cytidine deaminases, such as activation-induced deaminase and APOBEC1, either display a strong preference for editing deoxycytidines in other dinucleotide contexts or act on TC motifs in RNA (4), mutations that arise in a CC or TC context in DNA constitute signatures of editing by A3 proteins.Much headway has been made in understanding how A3 proteins act on HIV-1 DNA, in part through transfection of A3 plasmids into human epithelium-derived cell lines, such as 293T or HeLa cells, which lack significant endogenous expression of most A3 proteins. From such studies, A3G and APOBEC3F (A3F) are known to be packaged into virus particles when the HIV-1 Vif protein is not expressed and to cause a substantial reduction in virus infectivity (5, 12, 14 -16). Reduced virus infectivity results in part from non-enzymatic inhibition of reverse transcription by A3G and A3F (17-2...

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“…Vif simultaneously binds to APOBEC3 and to a cellular ubiquitin ligase (cullin5 [Cul5]-elongin [Elo]B/C-Rbx)) through distinct amino acids motifs (13,14). This binding induces the polyubiquitination of both APOBEC3 and Vif, which are then targeted for proteasomal degradation (3,(15)(16)(17)(18)(19)(20). This process depletes the pool of cytosolic APOBEC3 that is available for incorporation into assembling viral particles and reduces the risk of HIV-1 hypermutation in the next infected cell.…”

mentioning

confidence: 99%

“…Because of its small genome, high mutation rate, large population size, and rapid turnover rate, nearly all HIV-1 single-mutation variants are produced in most untreated hosts each day, and any variant with the slightest survival advantage rapidly prevails (1). The high mutation rate of HIV-1 has been linked to the high error rate of HIV-1 reverse transcriptase (RT) and RNA polymerase II (RNA Pol II) (2) and to innate cellular cytidine deaminases, such as apolipoprotein B mRNA-editing enzyme-catalytic polypeptidelike 3 (APOBEC3) (3).…”

mentioning

confidence: 99%

“…During reverse transcription, APOBEC3F and APOBEC3G induce cytidine-to-uridine (C-to-U) deamination of single-stranded minus-strand HIV-1 DNA, which generates guanosine-to-adenosine (G-to-A) mutations in plus-strand DNA (3,(5)(6)(7)(8)(9)(10)(11). These G-to-A mutations occur in APOBEC3F-and APOBEC3G-favored di-, tri-and tetranucleotide contexts (the GGnn-to-AGnn and GAnn-to-AAnn contexts, respectively [12]) (the mutated nucleotide residue is underlined).…”

mentioning

confidence: 99%

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Possible Footprints of APOBEC3F and/or Other APOBEC3 Deaminases, but Not APOBEC3G, on HIV-1 from Patients with Acute/Early and Chronic Infections

Armitage

Deforche

Welch

et al. 2014

J Virol

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Members of the apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like-3 (APOBEC3) innate cellular cytidine deaminase family, particularly APOBEC3F and APOBEC3G, can cause extensive and lethal G-to-A mutations in HIV-1 plusstrand DNA (termed hypermutation). It is unclear if APOBEC3-induced mutations in vivo are always lethal or can occur at sublethal levels that increase HIV-1 diversification and viral adaptation to the host. The viral accessory protein Vif counteracts APOBEC3 activity by binding to APOBEC3 and promoting proteasome degradation; however, the efficiency of this interaction varies, since a range of hypermutation frequencies are observed in HIV-1 patient DNA. Therefore, we examined "footprints" of APOBEC3G and APOBEC3F activity in longitudinal HIV-1 RNA pol sequences from approximately 3,000 chronically infected patients by determining whether G-to-A mutations occurred in motifs that were favored or disfavored by these deaminases. Gto-A mutations were more frequent in APOBEC3G-disfavored than in APOBEC3G-favored contexts. In contrast, mutations in APOBEC3F-disfavored contexts were relatively rare, whereas mutations in contexts favoring APOBEC3F (and possibly other deaminases) occurred 16% more often than average G-to-A mutations. These results were supported by analyses of >500 HIV-1 env sequences from acute/early infection. IMPORTANCECollectively, our results suggest that APOBEC3G-induced mutagenesis is lethal to HIV-1, whereas mutagenesis caused by APOBEC3F and/or other deaminases may result in sublethal mutations that might facilitate viral diversification. Therefore, Vifspecific cytotoxic T lymphocyte (CTL) responses and drugs that manipulate the interplay between Vif and APOBEC3 may have beneficial or detrimental clinical effects depending on how they affect the binding of Vif to various members of the APOBEC3 family.

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APOBEC proteins and intrinsic resistance to HIV-1 infection

Cited by 243 publications

References 138 publications

The nerve growth factor reduces APOBEC3G synthesis and enhances HIV-1 transcription and replication in human primary macrophages

The nerve growth factor reduces APOBEC3G synthesis and enhances HIV-1 transcription and replication in human primary macrophages

Innate Immune Signaling Induces High Levels of TC-specific Deaminase Activity in Primary Monocyte-derived Cells through Expression of APOBEC3A Isoforms

Possible Footprints of APOBEC3F and/or Other APOBEC3 Deaminases, but Not APOBEC3G, on HIV-1 from Patients with Acute/Early and Chronic Infections

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