Human cyclin T1 expression ameliorates a T-cell-specific transcriptional limitation for HIV in transgenic rats, but is not sufficient for a spreading infection of prototypic R5 HIV-1 strains ex vivo

Michel, Nico; Goffinet, Christine; Ganter, Kerstin; Allespach, Ina; KewalRamani, Vineet N.; Saifuddin, Mohammed; Littman, Dan R.; Greene, Warner C.; Goldsmith, Mark A.; Keppler, Oliver T.

doi:10.1186/1742-4690-6-2

Cited by 20 publications

(23 citation statements)

References 51 publications

(104 reference statements)

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“…10-to 100-fold lower than in human HeLa cells, indicating that additional limitations, including the nuclear export of viral RNA (2,34), hamper the overall late-phase efficiency for HIV-1 in rodent cells. Based on the current findings, we envision two independent strategies to enhance the permissivity of the hCD4/CCR5/cyclin T1-transgenic rat model (27,37). First, a knockout of CD317 in rats (21) provides the most direct approach to interfere with the activity of this antiviral restriction factor in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…In the context of efforts to establish fully permissive, immunocompetent rat (27,37) and mouse (3, 59) models of HIV infection, and given the ability of ectopically expressed rodent CD317 to inhibit HIV-1 release in a Vpu-resistant manner (10), we explored whether endogenous CD317 contributes to HIV-1 late-phase restriction in rodent cells. Depletion of CD317 by RNA interference markedly enhanced titers of wildtype HIV-1 secreted from Rat2 cells and also augmented the release of HIV-1 in infected primary rat macrophages.…”

Section: Discussionmentioning

confidence: 99%

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Endogenous CD317/Tetherin Limits Replication of HIV-1 and Murine Leukemia Virus in Rodent Cells and Is Resistant to Antagonists from Primate Viruses

Goffinet

Schmidt

Kern

et al. 2010

J Virol

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Human CD317 (BST-2/tetherin) is an intrinsic immunity factor that blocks the release of retroviruses, filoviruses, herpesviruses, and arenaviruses. It is unclear whether CD317 expressed endogenously in rodent cells has the capacity to interfere with the replication of the retroviral rodent pathogen murine leukemia virus (MLV) or, in the context of small-animal model development, contributes to the well-established late-phase restriction of human immunodeficiency virus type 1 (HIV-1). Here, we show that small interfering RNA (siRNA)-mediated knockdown of CD317 relieved a virion release restriction and markedly enhanced the egress of HIV-1, HIV-2, and simian immunodeficiency virus (SIV) in rat cells, including primary macrophages. Moreover, rodent CD317 potently inhibited MLV release, and siRNA-mediated depletion of CD317 in a mouse T-cell line resulted in the accelerated spread of MLV. Several virus-encoded antagonists have recently been reported to overcome the restriction imposed by human or monkey CD317, including HIV-1 Vpu, envelope glycoproteins of HIV-2 and Ebola virus, Kaposi's sarcoma-associated herpesvirus K5, and SIV Nef. In contrast, both rat and mouse CD317 showed a high degree of resistance to these viral antagonists. These data suggest that CD317 is a broadly acting and conserved mediator of innate control of retroviral infection and pathogenesis that restricts the release of retroviruses and lentiviruses in rodents. The high degree of resistance of the rodent CD317 restriction factors to antagonists from primate viruses has implications for HIV-1 smallanimal model development and may guide the design of novel antiviral interventions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Endogenous CD317/Tetherin Limits Replication of HIV-1 and Murine Leukemia Virus in Rodent Cells and Is Resistant to Antagonists from Primate Viruses

Goffinet

Schmidt

Kern

et al. 2010

J Virol

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“…Despite a high proviral load in lymphatic organs, the current transgenic rat model still has limitations, including low and transient viremia and lack of HIV disease. As in the case of mice, these problems are due to ill-defined late-phase barriers that limit HIV production, particularly in primary T cells (42,43,51).…”

mentioning

confidence: 99%

“…The ultimate goal is to use this knowledge to generate immunocompetent transgenic small animals that are fully permissive for HIV replication. We and others have characterized such barriers in the early phase of HIV replication in mouse and rat cells (8,32,43,50,51,72) and have successfully overcome them by transgenic expression of appropriate human cofactors (CD4, CCR5, CXCR4, and cyclin T1) in laboratory rodents (16,42,51,76). However, cells from triple-transgene mice are still resistant to infection (76).…”

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confidence: 99%

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High Natural Permissivity of Primary Rabbit Cells for HIV-1, with a Virion Infectivity Defect in Macrophages as the Final Replication Barrier

Tervo

Keppler

2010

J Virol

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An immunocompetent, permissive, small-animal model would be valuable for the study of human immunodeficiency virus type 1 (HIV-1) pathogenesis and for the testing of drug and vaccine candidates. However, the development of such a model has been hampered by the inability of primary rodent cells to efficiently support several steps of the HIV-1 replication cycle. Although transgenesis of the HIV receptor complex and human cyclin T1 have been beneficial, additional late-phase blocks prevent robust replication of HIV-1 in rodents and limit the range of in vivo applications. In this study, we explored the HIV-1 susceptibility of rabbit primary T cells and macrophages. Envelope-specific and coreceptor-dependent entry of HIV-1 was achieved by expressing human CD4 and CCR5. A block of HIV-1 DNA synthesis, likely mediated by TRIM5, was overcome by limited changes to the HIV-1 gag gene. Unlike with mice and rats, primary cells from rabbits supported the functions of the regulatory viral proteins Tat and Rev, Gag processing, and the release of HIV-1 particles at levels comparable to those in human cells. While HIV-1 produced by rabbit T cells was highly infectious, a macrophage-specific infectivity defect became manifest by a complex pattern of mutations in the viral genome, only part of which were deamination dependent. These results demonstrate a considerable natural HIV-1 permissivity of the rabbit species and suggest that receptor complex transgenesis combined with modifications in gag and possibly vif of HIV-1 to evade species-specific restriction factors might render lagomorphs fully permissive to infection by this pathogenic human lentivirus.

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Control of Innate and Adaptive Immune Responses during Infectious Diseases

Aliberti¹

2012

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Human cyclin T1 expression ameliorates a T-cell-specific transcriptional limitation for HIV in transgenic rats, but is not sufficient for a spreading infection of prototypic R5 HIV-1 strains ex vivo

Cited by 20 publications

References 51 publications

Endogenous CD317/Tetherin Limits Replication of HIV-1 and Murine Leukemia Virus in Rodent Cells and Is Resistant to Antagonists from Primate Viruses

Endogenous CD317/Tetherin Limits Replication of HIV-1 and Murine Leukemia Virus in Rodent Cells and Is Resistant to Antagonists from Primate Viruses

High Natural Permissivity of Primary Rabbit Cells for HIV-1, with a Virion Infectivity Defect in Macrophages as the Final Replication Barrier

Control of Innate and Adaptive Immune Responses during Infectious Diseases

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