Inhibition of HIV-1 replication by simian restriction factors, TRIM5α and APOBEC3G

Sakuma, Ryuta; Noser, Josh A.; Ohmine, Seiga; Ikeda, Yasuhiro

doi:10.1038/sj.gt.3302852

Cited by 29 publications

(16 citation statements)

References 38 publications

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“…The restrictive properties of TRIM5α have been proposed as the basis of anti-viral therapies [1,2,8,10,49]. Our results showing effective AgmTRIM5α-mediated restriction of HIV-1 and SIV mac239 in CD4 + T cells are consistent with the use of the TRIM5α restriction mechanism as an anti-HIV/SIV approach.…”

Section: Discussionsupporting

confidence: 88%

“…In contrast, single-round infectivity assays with pseudotyped defective viruses or viral vectors have found that rhTRIM5α strongly (>70- 95%) restricts HIV-1 infection, while AgmTRIM5α weakly (~60%) restricts SIV mac , with gorilla TRIM5α (gorTRIM5α) having a stronger effect (~90%) [22]. Despite a large body of infection experiments, only a few studies have examined TRIM5α restriction using wild-type viruses in cell-free replication assays [8,10,18,30,48,49]. …”

Section: Introductionmentioning

confidence: 99%

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Potent restriction of HIV-1 and SIVmac239 Replication by African Green Monkey TRIM5α

et al. 2015

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BackgroundThe TRIM5α protein is a principal restriction factor that contributes to an HIV-1 replication block in rhesus macaque CD4+ T cells by preventing reverse transcription. HIV-1 restriction is induced in human CD4+ T cells by expression of rhesus TRIM5α as well as those of other old world monkeys. While TRIM5α restriction has been extensively studied in single-round infection assays, fewer studies have examined restriction after extended viral replication.ResultsTo examine TRIM5α restriction of replication, we studied the ability of TRIM5α proteins from African green monkey (AgmTRIM5α) and gorilla (gorTRIM5α) to restrict HIV-1 and SIVmac239 replication. These xenogeneic TRIM5α genes were transduced into human Jurkat-CCR5 cells (JR5), which were then exposed to HIV-1 or SIVmac239. In our single-round infection assays, AgmTRIM5α showed a relatively modest 4- to 10-fold restriction of HIV-1 and SIVmac239, while gorTRIM5α produced a 2- and 3-fold restriction of HIV-1 and SIVmac239, respectively, consistent with the majority of previously published single-round studies. To assess the impact of these modest effects on infection, we tested restriction in replication systems initiated with either cell-free or cell-to-cell challenges. AgmTRIM5α powerfully restricted both HIV-1 and SIVmac239 replication 14 days after cell-free infection, with a ≥ 3-log effect. Moreover, expression of AgmTRIM5α restricted HIV-1 and SIVmac239 replication by 2-logs when co-cultured with infected JR5 cells for 12 days. In contrast, neither expression of gorTRIM5α nor rhesus TRIM5α induced significant resistance when co-cultured with infected cells. Follow up experiments showed that the observed differences between replication and infection were not due to assembly defects as xenogeneic TRIM5α expression had no effect on either virion production or specific infectivity.ConclusionsOur results indicate that AgmTRIM5α has a much greater effect on extended replication than on any single infection event, suggesting that AgmTRIM5α restriction acts cumulatively, building up over many rounds of replication. Furthermore, AgmTRIM5α was able to potently restrict both HIV-1 and SIV replication in a cell-to-cell infection challenge. Thus, AgmTRIM5α is unique among the TRIM5α species tested to date, being able to restrict even at the high multiplicities of infection presented by mixed culture with nonrestrictive infected cells.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Potent restriction of HIV-1 and SIVmac239 Replication by African Green Monkey TRIM5α

et al. 2015

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“…While selected by virus infections of the past, the strategies that primates have deployed to cope with lentiviruses, and an understanding of how such adaptations constrain virus fitness, may be exploited as novel therapeutic strategies to stem modern pandemics in humans. For example, the introduction of HIV-specific restriction factors into human cells is a burgeoning avenue for antiviral gene therapy [77][78][79]. However, the vast potential for viruses to counter-evolve in the face of genetic innovations of their hosts means that a combinatorial approach to gene therapy may prove most successful.…”

Section: Looking Backwards To Move Forwardmentioning

confidence: 99%

Host gene evolution traces the evolutionary history of ancient primate lentiviruses

Compton

Malik

Emerman

2013

Phil. Trans. R. Soc. B

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Simian immunodeficiency viruses (SIVs) have infected primate species long before human immunodeficiency virus has infected humans. Dozens of species-specific lentiviruses are found in African primate species, including two strains that have repeatedly jumped into human populations within the past century. Traditional phylogenetic approaches have grossly underestimated the age of these primate lentiviruses. Instead, here we review how selective pressures imposed by these viruses have fundamentally altered the evolutionary trajectory of hosts genes and, even in cases where there now remains no trace of the viruses themselves, these evolutionary signatures can reveal the types of viruses that were once present. Examination of selection by ancient viruses on the adaptive evolution of host genes has been used to derive minimum age estimates for modern primate lentiviruses. This type of data suggests that ancestors of modern SIV existed in simian primates more than 10 Ma. Moreover, examples of host resistance and viral adaptation have implications not only for estimating the age and host range of ancient primate lentiviruses, but also the pathogenic potential of their modern counterparts.

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“…These factors potentially restrict the permissivity of HIV-1-based lentiviral vectors in certain nonhuman primates, especially rhesus macaques, which provide an extensively utilized preclinical model for evaluating the safety and potential efficacy of viral vector strategies for gene therapy approaches to human disease. Among these restriction factors, tripartite motif-containing 5 isoform-␣ (TRIM5␣) and apolipoprotein B mRNA-editing catalytic polypeptide 3G (APOBEC3G) have both been shown to restrict HIV-1 infection and in combination may potentially decrease the transduction efficiency of HIV-1-based viral vectors (31). TRIM5␣ binds to the HIV-1 capsid (hCA) to initiate E3 ubiquitin ligasemediated degradation and prevent viral replication (37).…”

mentioning

confidence: 99%

Development of a Human Immunodeficiency Virus Type 1-Based Lentiviral Vector That Allows Efficient Transduction of both Human and Rhesus Blood Cells

Uchida

Washington

Hayakawa

et al. 2009

J Virol

144

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Human immunodeficiency virus type 1 (HIV-1) vectors transduce rhesus blood cells poorly due to a species-specific block by TRIM5␣ and APOBEC3G, which target HIV-1 capsid and viral infectivity factor (Vif), respectively. We sought to develop a lentiviral vector capable of transducing both human and rhesus blood cells by combining components of both HIV-1 and simian immunodeficiency virus (SIV), including SIV capsid (sCA) and SIV Vif. A chimeric HIV-1 vector including sCA (HIV) was superior to the conventional SIV in transducing a human blood cell line and superior to the conventional HIV-1 vector in transducing a rhesus blood cell line. Among human CD34؉ hematopoietic stem cells (HSCs), the HIV and HIV-1 vectors showed similar transduction efficiencies; in rhesus CD34 ؉ HSCs, the HIV vector yielded superior transduction rates. In in vivo competitive repopulation experiments with two rhesus macaques, the HIV vector demonstrated superior marking levels over the conventional HIV-1 vector in all blood lineages (first rhesus, 15 to 30% versus 1 to 5%; second rhesus, 7 to 15% versus 0.5 to 2%, respectively) 3 to 7 months postinfusion. In summary, we have developed an HIV-1-based lentiviral vector system that should allow comprehensive preclinical testing of HIV-1-based therapeutic vectors in the rhesus macaque model with eventual clinical application.

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Inhibition of HIV-1 replication by simian restriction factors, TRIM5α and APOBEC3G

Cited by 29 publications

References 38 publications

Potent restriction of HIV-1 and SIVmac239 Replication by African Green Monkey TRIM5α

Potent restriction of HIV-1 and SIVmac239 Replication by African Green Monkey TRIM5α

Host gene evolution traces the evolutionary history of ancient primate lentiviruses

Development of a Human Immunodeficiency Virus Type 1-Based Lentiviral Vector That Allows Efficient Transduction of both Human and Rhesus Blood Cells

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