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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, glyco-Gag 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 vivo—namely, 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.

Background The type I interferon (IFN) response is a critical component of the innate immune response to infection by RNA viruses and is initiated via recognition of viral nucleic acids by RIG-like receptors (RLR). Engagement of these receptors in the cytoplasm initiates a signal transduction pathway leading to activation of the transcription factors NF-κB, ATF-2 and IRF-3 that coordinately upregulate transcription of type I IFN genes, such as that encoding IFN-β. In this study the impact of poliovirus infection on the type I interferon response has been examined. Methods The type I IFN response was assessed by measuring IFN-β mRNA levels using qRT-PCR and normalizing to levels of β-actin mRNA. The status of host factors involved in activation of the type I IFN response was examined by immunoblot, immunofluorescence microcopy and qRT-PCR. Results The results show that poliovirus infection results in induction of very low levels of IFN-β mRNA despite clear activation of NF-κB and ATF-2. In contrast, analysis of IRF-3 revealed no transcriptional induction of an IRF-3-responsive promoter or homodimerization of IRF-3 indicating it is not activated in poliovirus-infected cells. Exposure of poliovirus-infected cells to poly(I:C) results in lower levels of IFN-β mRNA synthesis and IRF-3 activation compared to mock-infected cells. Analysis of MDA-5 and IPS-1 revealed that these components of the RLR pathway were largely intact at times when the type I IFN response was suppressed. Conclusions Collectively, these results demonstrate that poliovirus infection actively suppresses the host type I interferon response by blocking activation of IRF-3 and suggests that this is not mediated by cleavage of MDA-5 or IPS-1.

The type I interferon response is a powerful antiviral host defense against viral infection. Activation of the type I interferon response requires the coordinated action of the latent transcription factors NF-κB, IRF-3 and ATF-2 which in turn activate transcription from the IFN-β promoter. In this study the host type I interferon response to rhinovirus type 14 (RV14) and poliovirus (PV) is examined. In addition a method for the rapid detection and quantitation of poliovirus and rhinovirus sequences is developed. Analysis of the type I interferon response in RV14-infected lung epithelial cells revealed that although RV14 induces the activation of the transcription factors NF-κB and ATF-2, only very low levels of IFN-β mRNA are detected. Analysis of the status of IRF-3 revealed that this transcription factor is not activated in RV14-infected cells as evidenced by the lack of nuclear localization, homodimer formation and phosphorylation. Inhibition of viral protein synthesis following infection resulted in an increase in IFN-β mRNA levels indicating that viral gene products prevent induction of this pathway. These results indicate that RV14 infection inhibits the host type I interferon response by interfering with IRF-3 activation. To determine if this phenomenon extends to other picornaviruses, the type I interferon response in PV-infected cells was examined. The results indicate that PV also fails to induce high levels of IFN-β mRNA despite activation of NF-κB and ATF-2. Similar to RV14 infection, IRF-3 is not activated in poliovirus-infected cells as evidenced by the lack of homodimerization and transcriptional induction of the IRF-3 responsive transcript, ISG54. These results indicate that PV, like RV14, interferes with the activation of IRF-3 to inhibit the induction of IFN-β mRNA. Further, the effect of RV14 and PV on poly(I:C) mediated activation of the type I interferon response was examined. Interestingly, the results revealed that only PV can inhibit poly(I:C) induced IFN-β mRNA induction and IRF-3 homodimerization. Collectively, these results indicate that RV14 and PV target different regulatory points in the pathways that lead to activation of IRF-3 and by doing so prevent cells from mounting a strong antiviral defense.

Pancytopenia, a hematologic condition, is a decrease in all three blood cell lines. The two main etiologies include decreased production or increased destruction of cells, as seen in nutritional deficiencies or liver cirrhosis, respectively. Pancytopenia commonly presents with fever, splenomegaly, and lymphadenopathy. Initial workup includes complete blood count, metabolic panel, peripheral smear, anemia panel, erythrocyte sedimentation rate, C-reactive protein, and lactate dehydrogenase. Workup also involves excluding toxins, human immunodeficiency virus (HIV), drug effects, and infectious etiologies. Malignancies can cause impaired production of cell lines. For hematologic malignancies, a bone marrow biopsy is performed. In patients above the age of 55 who are diagnosed with acute leukemia, acute lymphoblastic leukemia (ALL) is known to make up approximately 20% of all cases. Furthermore, ALL requires the presence of more than 20% lymphoblasts seen on bone marrow biopsy. Treatment includes induction, consolidation, and maintenance chemotherapy. We report the case of a 63-year-old male with a history of liver cirrhosis from non-alcoholic fatty liver disease who presented for consultation due to pancytopenia without signs of fever or lymphadenopathy. Imaging revealed cirrhosis, ascites, and moderate splenomegaly while the workup for toxins, infections, and HIV was negative. He presented to the hospital with worsening anasarca and acutely worsening pancytopenia. Peripheral smear showed pancytopenia with no definitive blasts, whereas bone marrow biopsy revealed B-lymphoblastic leukemia. He was transferred to a tertiary center for induction chemotherapy but ultimately transitioned to supportive care due to intolerance. This case demonstrates the importance of having a high suspicion for leukemia with an acute decline in all three cell lines, thereby prompting a bone marrow biopsy. Although lacking in the literature, adult patients with ALL can present with splenomegaly without fever or lymphadenopathy. These examination findings are clinical clues to evaluate for underlying malignancies in patients with pancytopenia, although coexisting etiologies may exist. Lastly, peripheral smear alone is insufficient to screen for diagnosis of ALL as it can be normal despite bone marrow involvement.