Persistence of Viremia and Production of Neutralizing Antibodies Differentially Regulated by Polymorphic<i>APOBEC3</i>and<i>BAFF-R</i>Loci in Friend Virus-Infected Mice

Tsuji-Kawahara, Sachiyo; Chikaishi, Tomomi; Takeda, Eri; Kato, Maiko; Kinoshita, Saori; Kajiwara, Eiji; Takamura, Shiki; Miyazawa, Masaaki

doi:10.1128/jvi.02516-09

Cited by 30 publications

(77 citation statements)

References 55 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%

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%

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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“…1D, right panel). However, the average plasma number of F-MuLV genome was significantly (14). Each closed circle represents the actual value obtained from an individual mouse.…”

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confidence: 99%

“…Thus, AID-mediated SHM and CSR are not required for F-MuLV elimination. Plasma viremia and virus-neutralizing Ab were detected as described previously (14). While MT/MT mice remained viremic even at 16 weeks pi, AID Ϫ/Ϫ mice cleared viremia, albeit less quickly than the WT mice did (Fig.…”

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confidence: 99%

“…(E) Changes in serum F-MuLV-neutralizing titers of either the IgM class or IgG class in AID Ϫ/Ϫ (n ϭ 6) or WT (n ϭ 5) mice after FV inoculation. Mice were bled and neutralizing titers were determined as described previously (8,14). Each data point shows the mean Ϯ the standard error of the mean (SEM) calculated with values obtained from the five or six mice described above.…”

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confidence: 99%

“…AID Ϫ/Ϫ CB6F 1 mice were subjected to peptide immunization and challenged with FV, and sera were collected at 3 weeks pi and subjected to heat inactivation (14). To reproduce Ab production in infected mice, we examined the kinetics of anti-FV Ab production.…”

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confidence: 99%

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Class Switch Recombination and Somatic Hypermutation of Virus-Neutralizing Antibodies Are Not Essential for Control of Friend Retrovirus Infection

Kato

Tsuji-Kawahara

Kawasaki

et al. 2015

J Virol

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Susceptibilities to retroviral infections differ within a single host species as exemplified by the presence of slow or rapid progressors and elite controllers among individuals infected with human immunodeficiency virus (1). Friend virus (FV) infection of adult immunocompetent mice is useful to study the genetic, molecular, and cellular bases of resistance against retroviruses (2, 3). FV consists of replication-competent Friend murine leukemia virus (FMuLV) and defective spleen focus-forming virus (SFFV). In C57BL/6 (B6) mice homozygously possessing the resistant Fv2 allele (4), not only is SFFV-induced proliferation of infected erythroid progenitor cells limited, but they are also actively eliminated by cellular immune responses (5). CD4 ϩ T cells are required for SFFV elimination, while B-lymphocytes are required for F-MuLV elimination (5, 6). FV-susceptible (BALB/c ϫ B6)F 1 (CB6F 1 ) mice rapidly develop splenomegaly and succumb to leukemia within 2 months postinfection (pi), but they can be protected against FV by a single immunization with an F-MuLV-encoded CD4 ϩ T cell epitope, Env 462-479 (7). This vaccine-induced protection also requires B-lymphocytes, while FV-infected cells are eliminated in the absence of CD8 ϩ T cells (8). For the production of FV-neutralizing antibodies (Ab), CD11c ϩ dendritic cells and Myd88 that transduces signals from Toll-like receptors (TLR) are crucial (9). TLR7 senses retroviral entry (10) and inhibits virus replication over the first 5 days of infection through rapid production of nonneutralizing IgM (11). TLR7-deficient mice failed to generate germinal centers and IgM-negative (IgM Ϫ ) B cells upon FV infection (12), suggesting that immunoglobulin somatic hypermutation (SHM) and class switch recombination (CSR) are associated with neutralizing Ab production and FV control. To examine directly if SHM and CSR are required for FV neutralization, we utilized mice deficient in activation-induced cytidine deaminase (AID), a B cell-specific enzyme required for SHM and CSR (13).AID-deficient (AID Ϫ/Ϫ ) B6 and BALB/c mice were purchased from Riken BioResource Center, Tsukuba, Japan, and bred and maintained along with B cell-deficient MT/MT mice (5). Animal experiments were carried out in accordance with governmental and institutional regulations. To examine if SHM and CSR are required for Fv2-associated resistance, we infected wild-type (WT), MT/MT, and AID Ϫ/Ϫ B6 mice with 5,000 spleen focusforming units (SFFU) of FV that was free of lactate dehydrogenase-elevating virus (5). All MT/MT mice died within 20 weeks pi (Fig. 1A) without developing polycythemia (Fig. 1C), while AID Ϫ/Ϫ mice remained resistant. F-MuLV gp70 expression on expanding TER-119 Ϫ cells consistent with the development of F-MuLV-induced myeloid leukemia (5) was evident in MT/ MT but not in AID Ϫ/Ϫ mice (Fig. 1B). Thus, AID-mediated SHM and CSR are not required for F-MuLV elimination. Plasma viremia and virus-neutralizing Ab were detected as described previously (14). While MT/MT mice remained viremic even at 16 w...

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Immunoglobulin VH gene diversity and somatic hypermutation during SIV infection of rhesus macaques

et al. 2015

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B cell functional defects are associated with delayed neutralizing antibody development in pathogenic lentivirus infections. However, the timeframe for alterations in the antibody repertoire and somatic hypermutation (SHM) remains unclear. Here, we utilized the SIV/rhesus macaque (RM) model to investigate the dynamics of immunoglobulin VH gene diversity and SHM following infection. Three RMs were infected with SIVmac239 and VH1, VH3 and VH4 genes were amplified from peripheral blood at 0, 2, 6, 24 and 36 weeks post-infection for next-generation sequencing. Analysis of over 3.8 million sequences against currently available RM germline VH genes revealed a highly biased VH gene repertoire in outbred RMs. SIV infection did not significantly perturb the predominant IgG1 response, but overall immunoglobulin SHM declined during the course of SIV infection. Moreover, SHM at the AID deamination hotspot, WRC, rapidly decreased and was suppressed throughout SIV infection. In contrast, a transient increase in mutations at the APOBEC3G deamination hotspot, CCC, coincided with a spike in APOBEC3G expression during acute SIV infection. The results outline a timetable for altered VH gene repertoire and IgG SHM in the SIV/RM model and suggest a burst of APOBEC3G-mediated antibody SHM during acute SIV infection.

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Persistence of Viremia and Production of Neutralizing Antibodies Differentially Regulated by PolymorphicAPOBEC3andBAFF-RLoci in Friend Virus-Infected Mice

Cited by 30 publications

References 55 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

Class Switch Recombination and Somatic Hypermutation of Virus-Neutralizing Antibodies Are Not Essential for Control of Friend Retrovirus Infection

Immunoglobulin VH gene diversity and somatic hypermutation during SIV infection of rhesus macaques

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