762. Inhibition of HIV-1 Replication by Simian Intrinsic Restriction Factors, TRIM5alpha and APOBEC3G

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

doi:10.1016/j.ymthe.2006.08.846

Cited by 4 publications

(4 citation statements)

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“…For example, several intracellular mechanisms restrict cell infection by retroviruses (6). For HIV-1 and SIV-like viruses in human cells, APOBEC-3G, -3F, and related cytidine deaminases are packaged into virions which lack an appropriate Vif (viral infectivity factor) protein (30,99,153,157). The APOBEC proteins block infection during the infection of the next cell, although the precise mechanism is not known, as the primary enzymatic activity of the APOBEC, cytidine deamination, is not essential for the antiviral activity (7,84).…”

Section: Intracellular Host Range Restrictionsmentioning

confidence: 99%

Cross-Species Virus Transmission and the Emergence of New Epidemic Diseases

Parrish

Holmes

Morens

et al. 2008

Microbiol Mol Biol Rev

704

705

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SUMMARY Host range is a viral property reflecting natural hosts that are infected either as part of a principal transmission cycle or, less commonly, as “spillover” infections into alternative hosts. Rarely, viruses gain the ability to spread efficiently within a new host that was not previously exposed or susceptible. These transfers involve either increased exposure or the acquisition of variations that allow them to overcome barriers to infection of the new hosts. In these cases, devastating outbreaks can result. Steps involved in transfers of viruses to new hosts include contact between the virus and the host, infection of an initial individual leading to amplification and an outbreak, and the generation within the original or new host of viral variants that have the ability to spread efficiently between individuals in populations of the new host. Here we review what is known about host switching leading to viral emergence from known examples, considering the evolutionary mechanisms, virus-host interactions, host range barriers to infection, and processes that allow efficient host-to-host transmission in the new host population.

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Section: Intracellular Host Range Restrictionsmentioning

confidence: 99%

Cross-Species Virus Transmission and the Emergence of New Epidemic Diseases

Parrish

Holmes

Morens

et al. 2008

Microbiol Mol Biol Rev

704

705

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“…Viral vectors will inevitably express A3G in the producer cells, and its incorporation into virions will inactivate the vector and the vector-encoded A3G. Previous gene therapy studies have proposed to utilize A3G to block HIV-1 replication by inhibiting A3G ubiquitination, 28 increasing virion incorporation of Vif-resistant A3G mutants, 29,30 expressing an HIV-1 Vif-resistant African green monkey A3G, 31 and using an inducible promoter to block expression of A3G in the producer cells. 32 Each of these studies tried to avert the potent inhibitory effects of A3G in the virus-producing cells but faced difficulties in achieving efficient delivery of A3G to target cells.…”

Section: Introductionmentioning

confidence: 99%

Development of Lentiviral Vectors for HIV-1 Gene Therapy with Vif-Resistant APOBEC3G

Delviks-Frankenberry

Ackerman

Timberlake

et al. 2019

Molecular Therapy - Nucleic Acids

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Strategies to control HIV-1 replication without antiviral therapy are needed to achieve a functional cure. To exploit the innate antiviral function of restriction factor cytidine deaminase APOBEC3G (A3G), we developed self-activating lentiviral vectors that efficiently deliver HIV-1 Vif-resistant mutant A3G-D128K to target cells. To circumvent APOBEC3 expression in virus-producing cells, which diminishes virus infectivity, a vector containing two overlapping fragments of A3G-D128K was designed that maintained the gene in an inactive form in the virus-producer cells. However, during transduction of target cells, retroviral recombination between the direct repeats reconstituted an active A3G-D128K in 89%–98% of transduced cells. Lentiviral vectors that expressed A3G-D128K transduced CD34+ hematopoietic stem and progenitor cells with a high efficiency (>30%). A3G-D128K expression in T cell lines CEM, CEMSS, and PM1 potently inhibited spreading infection of several HIV-1 subtypes by C-to-U deamination leading to lethal G-to-A hypermutation and inhibition of reverse transcription. SIVmac239 and HIV-2 were not inhibited, since their Vifs degraded A3G-D128K. A3G-D128K expression in CEM cells potently suppressed HIV-1 replication for >3.5 months without detectable resistant virus, suggesting a high genetic barrier for the emergence of A3G-D128K resistance. Because of this, A3G-D128K expression in HIV-1 target cells is a potential anti-HIV gene therapy approach that could be combined with other therapies for the treatment and functional cure of HIV-1 infection.

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“…10,11 TRIM5α recognizes retroviral capsids in combination with cyclophilin A (CypA) to degrade retrovirus in a species-specific manner. 12 In retroviral infection in rhesus macaques, rhesus TRIM5α recognizes the human immunodeficiency virus type 1 (HIV-1) capsid to degrade HIV-1, while the simian immunodeficiency virus (SIV) capsid can escape from rhesus TRIM5α restriction by attaching to rhesus CypA. We previously developed chimeric HIV-1-based lentiviral vectors (χHIV vectors) in which the HIV-1 vector genome is packaged in the context of the SIV capsid permitting escape from rhesus TRIM5α restriction.…”

Section: Introductionmentioning

confidence: 99%

TRIM5α Variations Influence Transduction Efficiency With Lentiviral Vectors in Both Human and Rhesus CD34+ Cells In Vitro and In Vivo

et al. 2014

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Human immunodeficiency virus type 1 (HIV-1) vectors can transduce human hematopoietic stem cells (HSC), but transduction efficiency varies among individuals. The innate immune factor tripartite motif-containing protein 5α (TRIM5α) plays an important role for restriction of retroviral infection. In this study, we examined whether TRIM5α could account for variations in transduction efficiency using both an established rhesus gene therapy model and human CD34(+) cell culture. Evaluation of TRIM5α genotypes (Mamu-1, -2, -3, -4, -5, and TrimCyp) in 16 rhesus macaques that were transplanted with transduced CD34(+) cells showed a significant correlation between TRIM5α Mamu-4 and high gene marking in both lymphocytes and granulocytes 6 months after transplantation. Since significant human TRIM5α coding polymorphisms were not known, we evaluated TRIM5α expression levels in human CD34(+) cells from 14 donors. Three days after HIV-1 vector transduction, measured transduction efficiency varied significantly among donors and was negatively correlated with TRIM5α expression levels. In summary, transduction efficiency in both rhesus and human CD34(+) cells was influenced by TRIM5α variations (genotypes and expression levels). Our findings are important for both understanding and mitigating the variability of transduction efficiency for rhesus and human CD34(+) cells.

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762. Inhibition of HIV-1 Replication by Simian Intrinsic Restriction Factors, TRIM5alpha and APOBEC3G

Cited by 4 publications

References 0 publications

Cross-Species Virus Transmission and the Emergence of New Epidemic Diseases

Cross-Species Virus Transmission and the Emergence of New Epidemic Diseases

Development of Lentiviral Vectors for HIV-1 Gene Therapy with Vif-Resistant APOBEC3G

TRIM5α Variations Influence Transduction Efficiency With Lentiviral Vectors in Both Human and Rhesus CD34+ Cells In Vitro and In Vivo

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