<i>Apobec3</i>
            Encodes
            <i>Rfv3</i>
            , a Gene Influencing Neutralizing Antibody Control of Retrovirus Infection

Santiago, Mario L.; Montaño, Mauricio; Benitez, Robert; Messer, Ronald J.; Yonemoto, Wes; Chesebro, Bruce; Hasenkrug, Kim J.; Greene, Warner C.

doi:10.1126/science.1161121

Cited by 126 publications

(249 citation statements)

References 25 publications

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“…Several studies have suggested that APOBEC BALB is less effective that APOBEC BL6 at restricting infection by F-MLV (27,30,50). However, clearly both alleles are important anti-M-MLV restriction factors, because reversion occurred with similar kinetics and frequency in the two mouse strains, and both alleles effectively inhibited reverse transcription in EnRT assays.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies showed that APOBEC3 BL6 more potently restricts F-MLV than the APOBEC3 BALB allele and that glyco-Gag mutant F-MLV replicates more poorly in WT mice bearing either allele than in APOBEC3 KO mice (8,27,30). To determine whether this was also the case for M-MLV, we infected C57BL/6, BALB/c, and APOBEC3 KO pups with WT and glyco-Gag mutant M-MLV; the APOBEC3 null allele is present on the BL/6 background (26).…”

Section: Resultsmentioning

confidence: 99%

“…There are also amino acid sequence changes in the conserved exons of the two alleles (30)(31)(32). APOBEC3 BL6 restricts infection by MMTV, F-MLV, and AKV more effectively than APOBEC BALB (27,(29)(30)(31). Interestingly, mouse APOBEC3 does not hypermutate viral DNA in F-MLV-, M-MLV-, or MMTV-infected cells but instead inhibits infection at an earlier replication step (21,26,29,30,(33)(34)(35).…”

mentioning

confidence: 98%

“…Mouse APOBEC3 also restricts endemic murine viruses, including mouse mammary tumor virus (MMTV), F-MLV, M-MLV, and AKR-MLV (AKV); this has been demonstrated in vivo in APOBEC3 KO mice (26)(27)(28)(29). Although there is only one mouse APOBEC3 gene, different inbred strains of mice carry variant alleles (30)(31)(32).…”

mentioning

confidence: 99%

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Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

Stavrou

Nitta

Kotla

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

194

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Pathogenic retroviruses have evolved multiple means for evading host restriction factors such as apolipoprotein B editing complex (APOBEC3) proteins. Here, we show that murine leukemia virus (MLV) has a unique means of counteracting APOBEC3 and other cytosolic sensors of viral nucleic acid. Using virus isolated from infected WT and APOBEC3 KO mice, we demonstrate that the MLV glycosylated Gag protein (glyco-Gag) enhances viral core stability. Moreover, in vitro endogenous reverse transcription reactions of the glyco-Gag mutant virus were substantially inhibited compared with WT virus, but only in the presence of APOBEC3. Thus, glyco-Gag rendered the reverse transcription complex in the viral core resistant to APOBEC3. Glyco-Gag in the virion also rendered MLV resistant to other cytosolic sensors of viral reverse transcription products in newly infected cells. Strikingly, glycoGag mutant virus reverted to glyco-Gag-containing virus only in WT and not APOBEC3 KO mice, indicating that counteracting APOBEC3 is the major function of glyco-Gag. Thus, in contrast to the HIV viral infectivity factor protein, which prevents APOBEC3 packaging in the virion, the MLV glyco-Gag protein uses a unique mechanism to counteract the antiviral action of APOBEC3 in vivonamely, protecting the reverse transcription complex in viral cores from APOBEC3. These data suggest that capsid integrity may play a critical role in virus resistance to intrinsic cellular antiviral resistance factors that act at the early stages of infection.intrinsic immunity | trex1 | virus restriction factors

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Section: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 98%

mentioning

confidence: 99%

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Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

Stavrou

Nitta

Kotla

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

194

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“…The debate over the mechanism of resistance to murine A3 (muA3) of the rodent gammaretrovirus Moloney murine leukemia virus (Mo-MLV) has not come up with a generally convincing model, despite many studies (5, 9, 13, 32, 35, 49). However, recent data clearly show that muA3 is an important in vivo restriction factor of Mo-MLV and the Friend virus complex (45,73,89).…”

mentioning

confidence: 99%

Restriction of Equine Infectious Anemia Virus by Equine APOBEC3 Cytidine Deaminases

Zielonka

Bravo²,

Marino

et al. 2009

J Virol

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The mammalian APOBEC3 (A3) proteins comprise a multigene family of cytidine deaminases that act as potent inhibitors of retroviruses and retrotransposons. The A3 locus on the chromosome 28 of the horse genome contains multiple A3 genes: two copies of A3Z1, five copies of A3Z2, and a single copy of A3Z3, indicating a complex evolution of multiple gene duplications. We have cloned and analyzed for expression the different equine A3 genes and examined as well the subcellular distribution of the corresponding proteins. Additionally, we have tested the functional antiretroviral activity of the equine and of several of the human and nonprimate A3 proteins against the Equine infectious anemia virus (EIAV), the Simian immunodeficiency virus (SIV), and the Adeno-associated virus type 2 (AAV-2). Hematopoietic cells of horses express at least five different A3s: A3Z1b, A3Z2a-Z2b, A3Z2c-Z2d, A3Z2e, and A3Z3, whereas circulating macrophages, the natural target of EIAV, express only part of the A3 repertoire. The five A3Z2 tandem copies arose after three consecutive, recent duplication events in the horse lineage, after the split between Equidae and Carnivora. The duplicated genes show different antiviral activities against different viruses: equine A3Z3 and A3Z2c-Z2d are potent inhibitors of EIAV while equine A3Z1b, A3Z2a-Z2b, A3Z2e showed only weak anti-EIAV activity. Equine A3Z1b and A3Z3 restricted AAV and all equine A3s, except A3Z1b, inhibited SIV. We hypothesize that the horse A3 genes are undergoing a process of subfunctionalization in their respective viral specificities, which might provide the evolutionary advantage for keeping five copies of the original gene.The Equine infectious anemia virus (EIAV) (family Retroviridae, genus Lentivirus) infects equids almost worldwide, causing a persistent infection characterized by recurring viremia, fever, thrombocytopenia, and wasting symptoms (40). EIAV infections are used as a model for natural immunologic control of lentivirus replication and virus persistence and as a test system to improve vaccines against lentiviruses (10,40,41,82). In vivo EIAV replicates predominantly in macrophages (77). Interaction with the equine lentiviral receptor 1 (ELR1) has been demonstrated to be responsible for EIAV internalization (96). There have been no reported cases of EIAV infections in humans, suggesting that it is an intrinsically safe virus and of interest for use in a clinical setting. Therefore, EIAV-based lentiviral vectors for human gene therapy were recently developed (1, 67, 68).In the last few years, two cellular proteins that inhibit many different retroviruses have been characterized: tripartite motif protein 5 alpha (TRIM5␣) and apolipoprotein B mRNAediting enzyme-catalytic polypeptide 3 (APOBEC3 [A3]) (for a review, see reference 92). With respect to TRIM5␣ proteins, both human and nonhuman primate TRIM5␣ orthologues can restrict infection by EIAV (26,72). The activity of equine TRIM5␣ on EIAV infection, however, has not been described so far. With respect to A3 proteins...

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APOBEC3 enzymes restrict marginal zone B cells

et al. 2015

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In general, a long-lasting immune response to viruses is achieved when they are infectious and replication-competent. In the mouse, the neutralizing antibody response to Friend murine leukemia virus is contributed by an allelic form of the enzyme Apobec3 (abbreviated A3). This is counterintuitive, because A3 directly controls viremia before the onset of adaptive anti-viral immune responses. It suggests that A3 also affects the antibody response directly. Here we studied the relative size of cell populations of the adaptive immune system as a function of A3 activity. We created a transgenic mouse that expresses all seven human A3 enzymes (hA3) and compared it to wild-type and mouse A3 (mA3)-deficient mice. A3 enzymes decreased the number of marginal zone (MZ) B cells, but not the number of follicular B or T cells. When mA3 was knocked out, the retroelement hitchhiker-1 and sialyl transferases encoded by genes close to it were overexpressed three and two orders of magnitude, respectively. We suggest that A3 shifts the balance, from the fast antibody response mediated by MZ B cells with little affinity maturation, to a more sustained germinal center B-cell response, which drives affinity maturation and, thereby, a better neutralizing response.

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Apobec3 Encodes Rfv3 , a Gene Influencing Neutralizing Antibody Control of Retrovirus Infection

Cited by 126 publications

References 25 publications

Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

Restriction of Equine Infectious Anemia Virus by Equine APOBEC3 Cytidine Deaminases

APOBEC3 enzymes restrict marginal zone B cells

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