Persistent Friend Virus Replication and Disease in
            <i>Apobec3</i>
            -Deficient Mice Expressing Functional B-Cell-Activating Factor Receptor

Santiago, Mario L.; Smith, Diana S.; Barrett, Bradley S.; Montaño, Mauricio; Benitez, Robert; Pelanda, Roberta; Hasenkrug, Kim J.; Greene, Warner C.

doi:10.1128/jvi.01838-10

Cited by 21 publications

(52 citation statements)

References 48 publications

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“…F-MuLV RNA copy numbers in the plasma were measured by quantitative PCR (22, 31). RNA extracted from 5 μl of plasma was added to 1× One-Step Taqman Reverse Transcriptase-PCR reaction mixture (Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

“…Over the last five decades, numerous genetic factors that influence FV resistance and susceptibility have been identified (14). These genes include Fv1 , which mediates a capsid-dependent post-entry block (16); Fv2 , a dominant susceptibility gene that dictates splenomegaly induction (17); H-2 , the murine MHC which controls adaptive immune responses (18, 19); and Apobec3/Rfv3 , which influences recovery from viremia by promoting a stronger neutralizing antibody response (20-22). …”

Section: Introductionmentioning

confidence: 99%

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Tetherin Promotes the Innate and Adaptive Cell–Mediated Immune Response against Retrovirus Infection In Vivo

Barrett

Heilman

et al. 2014

The Journal of Immunology

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Tetherin/BST-2 is a host restriction factor that could directly inhibit retroviral particle release by tethering nascent virions to the plasma membrane. However, the immunological impact of Tetherin during retrovirus infection remains unknown. We now show that Tetherin influences antiretroviral cell-mediated immune responses. In contrast to the direct antiviral effects of Tetherin, which are dependent on cell surface expression, the immunomodulatory effects are linked to the endocytosis of the molecule. Mice encoding endocytosis-competent C57BL/6 Tetherin exhibited lower viremia and pathology at 7 days post-infection with Friend retrovirus (FV) compared to mice encoding endocytosis-defective NZW/LacJ Tetherin. Notably, antiretroviral protection correlated with stronger NK cell responses. In addition, FV infection levels were significantly lower in wild-type C57BL/6 mice than in Tetherin knock-out mice at 2 weeks post-infection, and antiretroviral protection correlated with stronger NK cell and virus-specific CD8+ T cell responses. The results demonstrate that Tetherin acts as a modulator of the cell-mediated immune response against retrovirus infection in vivo.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tetherin Promotes the Innate and Adaptive Cell–Mediated Immune Response against Retrovirus Infection In Vivo

Barrett

Heilman

et al. 2014

The Journal of Immunology

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“…We showed that deletion of B6 mA3 in (B6 ϫ A.BY)F 1 mice resulted in weaker NAb responses and abrogated recovery from viremia and disease by 28 days postinfection (dpi) (14,17). Removal of B6 mA3 in a pure B6 genetic background also resulted in weaker NAb responses (14,15).…”

mentioning

confidence: 93%

Requirement for Fc Effector Mechanisms in the APOBEC3/Rfv3-Dependent Neutralizing Antibody Response

Halemano

Barrett

Heilman

et al. 2015

J Virol

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Antiretroviral neutralizing antibody (NAb) responses are often evaluated in the absence of Fc-dependent immune effectors. In murine Friend retrovirus infection, Apobec3/Rfv3 promotes a potent polyclonal NAb response. Here, we show that the Apobec3/Rfv3-dependent NAb response correlated with virus-specific IgG2 titers and that thein vivoneutralization potency of Apobec3/Rfv3-resistant antisera was dependent on activating Fcγ receptors but not complement. The data strengthen retroviral vaccine strategies aimed at eliciting NAbs that activate specific Fcγ receptors.

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“…Athymic nude (Ncr-nu/nu) mice were obtained from the National Cancer Institute (NCI). C57BL/6J Apobec3 knockout (B6 Apobec3 Ϫ/Ϫ ) mice were generated previously (50). This animal study has been approved by the Institutional Animal Care and Use Committee at the University of Colorado [approval number 93913(12)1E].…”

Section: Methodsmentioning

confidence: 99%

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

Warren

Guo

et al. 2015

J Virol

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Human papillomaviruses (HPVs) are small DNA viruses causally associated with benign warts and multiple cancers, including cervical and head-and-neck cancers. While the vast majority of people are exposed to HPV, most instances of infection are cleared naturally. However, the intrinsic host defense mechanisms that block the early establishment of HPV infections remain mysterious. Several antiviral cytidine deaminases of the human APOBEC3 (hA3) family have been identified as potent viral DNA mutators. While editing of HPV genomes in benign and premalignant cervical lesions has been demonstrated, it remains unclear whether hA3 proteins can directly inhibit HPV infection. Interestingly, recent studies revealed that HPV-positive cervical and head-and-neck cancers exhibited higher rates of hA3 mutation signatures than most HPV-negative cancers. Here, we report that hA3A and hA3B expression levels are highly upregulated in HPV-positive keratinocytes and cervical tissues in early stages of cancer progression, potentially through a mechanism involving the HPV E7 oncoprotein. HPV16 virions assembled in the presence of hA3A, but not in the presence of hA3B or hA3C, have significantly decreased infectivity compared to HPV virions assembled without hA3A or with a catalytically inactive mutant, hA3A/E72Q. Importantly, hA3A knockdown in human keratinocytes results in a significant increase in HPV infectivity. Collectively, our findings suggest that hA3A acts as a restriction factor against HPV infection, but the induction of this restriction mechanism by HPV may come at a cost to the host by promoting cancer mutagenesis. IMPORTANCEHuman papillomaviruses (HPVs) are highly prevalent and potent human pathogens that cause >5% of all human cancers, including cervical and head-and-neck cancers. While the majority of people become infected with HPV, only 10 to 20% of infections are established as persistent infections. This suggests the existence of intrinsic host defense mechanisms that inhibit viral persistence. Using a robust method to produce infectious HPV virions, we demonstrate that hA3A, but not hA3B or hA3C, can significantly inhibit HPV infectivity. Moreover, hA3A and hA3B were coordinately induced in HPV-positive clinical specimens during cancer progression, likely through an HPV E7 oncoprotein-dependent mechanism. Interestingly, HPV-positive cervical and head-and-neck cancer specimens were recently shown to harbor significant amounts of hA3 mutation signatures. Our findings raise the intriguing possibility that the induction of this host restriction mechanism by HPV may also trigger hA3A-and hA3B-induced cancer mutagenesis. Human papillomaviruses (HPVs) are small, nonenveloped DNA viruses known as one of the most prevalent sexually transmitted pathogens. Among almost 200 different genotypes, ϳ24 high-risk HPV genotypes are causally associated with multiple human cancers, including nearly all cervical cancers and a portion of head-and-neck squamous cell carcinomas (1). From 1988 to 2004, the incidence of HPV-associ...

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Persistent Friend Virus Replication and Disease in Apobec3 -Deficient Mice Expressing Functional B-Cell-Activating Factor Receptor

Cited by 21 publications

References 48 publications

Tetherin Promotes the Innate and Adaptive Cell–Mediated Immune Response against Retrovirus Infection In Vivo

Tetherin Promotes the Innate and Adaptive Cell–Mediated Immune Response against Retrovirus Infection In Vivo

Requirement for Fc Effector Mechanisms in the APOBEC3/Rfv3-Dependent Neutralizing Antibody Response

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

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