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The Curious Case of Type I IFN and MxA: Tipping the Immune Balance in AIDS.

Furuya AK, Sharifi HJ, de Noronha CM - Front Immunol (2014)

View Article: PubMed Central - PubMed

Affiliation: Albany Medical Center, Center for Immunology and Microbial Disease , Albany, NY , USA.

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Although HIV preferentially infects CD4 T cells and macrophages, efficient binding and infection of pDCs by HIV have been demonstrated and may contribute to AIDS pathogenesis... Plasmacytoid dendritic cells are specialized cells found in blood and lymphoid tissues... They are produced upon viral infection, replication, and/or the introduction of double-stranded RNA... IFNs trigger antiviral activity and induce the maturation of effector T cells... One common denominator is the myxovirus resistance protein (MxA or Mx1) gene... This finding was supported by a recent clinical study in which Chang et al. found that persistent higher expression of type I IFN and ISGs, including MxA, may explain, at least in part, the increased immune activation and more rapid disease progression in females with chronic HIV infections when compared to males with similar viral loads... Harris et al. convincingly showed that natural hosts African green monkeys (AGM) and SM begin to downregulate MxA responses by 28 dpi whereas non-natural hosts (RM) maintained high levels of MxA in LN... This work, however, did not reveal a mechanism of IFN I resolution... Most species have one to three Mx protein isoforms with different antiviral activity depending on their intracellular localization... Mouse Mx1 protein is found primarily in the nucleus whereas human MxA is cytoplasmic... Human MxA can be induced by IFN or directly by the virus through different pathways... As mentioned previously, in contrast to non-natural hosts, natural SIV hosts downregulate MxA responses during the transition to chronic infection despite high viremia... Additionally, the virus may synergize with IFN to increase Mx levels... Studying variations in the Mx genes, simultaneously with standardized screening of their antiviral properties in natural and non-natural SIV hosts, could explain why natural hosts can downregulate MxA responses with the onset of the chronic stage of infection... Evidence supporting a role for MxA genes, warrants studying polymorphisms in MxA genes, which may shed light on the mechanism of active IFN downregulation.

No MeSH data available.


Related in: MedlinePlus

Schematic of IFN and Mx protein regulation in acute and chronic SIV infection models.
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Figure 1: Schematic of IFN and Mx protein regulation in acute and chronic SIV infection models.

Mentions: What are Mx proteins and how do they exert their antiviral activity? Most importantly, how are Mx proteins involved in SIV/HIV infections? Mx proteins belong to the superfamily of GTPases, which includes dynamins, dynamin-like proteins, and mitofusins [described in more detail in Ref. (33)]. These proteins are involved in endocytosis, intracellular vesicle transport, and mitochondria distribution. Mx proteins are mainly characterized by three conserved domains: an N-terminal GTPase domain (GTP binding), a middle domain responsible for interaction with the GTPase effector domain (GED), and the C-terminus GED domain, which recognizes the virus. Two amphipatic α-helices form leucine zippers in the C-terminus. Furthermore, Mx proteins can self-assemble into higher order ring-like structures to form a helical stack (28). The higher order structures may represent a storage form whereas the monomers are likely the active form of MxA (34). Human MxA can be induced by IFN or directly by the virus through different pathways. Activation of Mx by IFN involves the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and the formation of an IFN-stimulated gene factor 3 (ISGF3) multimeric complex, which in turn migrates into the nucleus and binds an IFN-stimulated response element (ISRE) upstream of the Mx gene (35, 36). It is not yet clear how viral infection activates Mx but it seems to be independent of ISGF3, involving STAT1 instead and possibly the IFN-regulatory factors 1 and 3 (IRF1 and IRF3) (37–39). Mx gene activation is fast. Its protein product is detectable within 4 h (40). It is thus likely that Mx gene activation in response to both virus and IFN through two different pathways is evolutionarily advantageous to the host. Indeed HIV can induce MxA transcription and activate ISGs independently of IFN (41). As mentioned previously, in contrast to non-natural hosts, natural SIV hosts downregulate MxA responses during the transition to chronic infection despite high viremia (24). Moreover with every upregulation/activation, there must be a downregulation of the response in order to maintain homeostasis. Indeed overexpression of MxA is a common pathogenic link in Fanconi Anemia (FA), which consists of a group of at least five autosomal recessive disorders. Overexpression of MxA can lead to cancer susceptibility, apoptosis, bone marrow failure, and abnormal instability in cells (42). One potential mechanism for regulation of Mx gene expression relies on the IRF-1 and IRF-2 proteins. The most probable mediator of Mx induction is IRF-1, which is increased in the presence of virus and after IFN treatment (43, 44). This suggests that the functional synergy between the two independent pathways converges in upregulation of Mx. Additionally, the virus may synergize with IFN to increase Mx levels. IRF-1 induces IRF-2 production to repress ISG transcription. This in turn inhibits IRF-1 function. IRF-1 and IRF-2 share homology in their DNA binding domain; however, IRF-2 has higher affinity for binding and a longer half-life (45). Interestingly, IRF-2 also protects quiescent hematopoietic stem cells (HSC) from type I IFN exhaustion (46). In order to avoid cancer susceptibility, increased apoptosis, bone marrow failure, and HSC depletion, natural SIV hosts apparently evolved to control the IFN responses (Figure 1); however, the exact mechanism is not yet clear. Studying variations in the Mx genes, simultaneously with standardized screening of their antiviral properties in natural and non-natural SIV hosts, could explain why natural hosts can downregulate MxA responses with the onset of the chronic stage of infection. Additionally, mining for polymorphisms in regulatory genes, such as IRF-2, which correlate with enhanced DNA binding or half-life of the activated protein may offer an avenue for designing new therapeutics for controlling the immune system hyperactivation that is associated with AIDS progression.


The Curious Case of Type I IFN and MxA: Tipping the Immune Balance in AIDS.

Furuya AK, Sharifi HJ, de Noronha CM - Front Immunol (2014)

Schematic of IFN and Mx protein regulation in acute and chronic SIV infection models.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4151092&req=5

Figure 1: Schematic of IFN and Mx protein regulation in acute and chronic SIV infection models.
Mentions: What are Mx proteins and how do they exert their antiviral activity? Most importantly, how are Mx proteins involved in SIV/HIV infections? Mx proteins belong to the superfamily of GTPases, which includes dynamins, dynamin-like proteins, and mitofusins [described in more detail in Ref. (33)]. These proteins are involved in endocytosis, intracellular vesicle transport, and mitochondria distribution. Mx proteins are mainly characterized by three conserved domains: an N-terminal GTPase domain (GTP binding), a middle domain responsible for interaction with the GTPase effector domain (GED), and the C-terminus GED domain, which recognizes the virus. Two amphipatic α-helices form leucine zippers in the C-terminus. Furthermore, Mx proteins can self-assemble into higher order ring-like structures to form a helical stack (28). The higher order structures may represent a storage form whereas the monomers are likely the active form of MxA (34). Human MxA can be induced by IFN or directly by the virus through different pathways. Activation of Mx by IFN involves the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and the formation of an IFN-stimulated gene factor 3 (ISGF3) multimeric complex, which in turn migrates into the nucleus and binds an IFN-stimulated response element (ISRE) upstream of the Mx gene (35, 36). It is not yet clear how viral infection activates Mx but it seems to be independent of ISGF3, involving STAT1 instead and possibly the IFN-regulatory factors 1 and 3 (IRF1 and IRF3) (37–39). Mx gene activation is fast. Its protein product is detectable within 4 h (40). It is thus likely that Mx gene activation in response to both virus and IFN through two different pathways is evolutionarily advantageous to the host. Indeed HIV can induce MxA transcription and activate ISGs independently of IFN (41). As mentioned previously, in contrast to non-natural hosts, natural SIV hosts downregulate MxA responses during the transition to chronic infection despite high viremia (24). Moreover with every upregulation/activation, there must be a downregulation of the response in order to maintain homeostasis. Indeed overexpression of MxA is a common pathogenic link in Fanconi Anemia (FA), which consists of a group of at least five autosomal recessive disorders. Overexpression of MxA can lead to cancer susceptibility, apoptosis, bone marrow failure, and abnormal instability in cells (42). One potential mechanism for regulation of Mx gene expression relies on the IRF-1 and IRF-2 proteins. The most probable mediator of Mx induction is IRF-1, which is increased in the presence of virus and after IFN treatment (43, 44). This suggests that the functional synergy between the two independent pathways converges in upregulation of Mx. Additionally, the virus may synergize with IFN to increase Mx levels. IRF-1 induces IRF-2 production to repress ISG transcription. This in turn inhibits IRF-1 function. IRF-1 and IRF-2 share homology in their DNA binding domain; however, IRF-2 has higher affinity for binding and a longer half-life (45). Interestingly, IRF-2 also protects quiescent hematopoietic stem cells (HSC) from type I IFN exhaustion (46). In order to avoid cancer susceptibility, increased apoptosis, bone marrow failure, and HSC depletion, natural SIV hosts apparently evolved to control the IFN responses (Figure 1); however, the exact mechanism is not yet clear. Studying variations in the Mx genes, simultaneously with standardized screening of their antiviral properties in natural and non-natural SIV hosts, could explain why natural hosts can downregulate MxA responses with the onset of the chronic stage of infection. Additionally, mining for polymorphisms in regulatory genes, such as IRF-2, which correlate with enhanced DNA binding or half-life of the activated protein may offer an avenue for designing new therapeutics for controlling the immune system hyperactivation that is associated with AIDS progression.

View Article: PubMed Central - PubMed

Affiliation: Albany Medical Center, Center for Immunology and Microbial Disease , Albany, NY , USA.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Although HIV preferentially infects CD4 T cells and macrophages, efficient binding and infection of pDCs by HIV have been demonstrated and may contribute to AIDS pathogenesis... Plasmacytoid dendritic cells are specialized cells found in blood and lymphoid tissues... They are produced upon viral infection, replication, and/or the introduction of double-stranded RNA... IFNs trigger antiviral activity and induce the maturation of effector T cells... One common denominator is the myxovirus resistance protein (MxA or Mx1) gene... This finding was supported by a recent clinical study in which Chang et al. found that persistent higher expression of type I IFN and ISGs, including MxA, may explain, at least in part, the increased immune activation and more rapid disease progression in females with chronic HIV infections when compared to males with similar viral loads... Harris et al. convincingly showed that natural hosts African green monkeys (AGM) and SM begin to downregulate MxA responses by 28 dpi whereas non-natural hosts (RM) maintained high levels of MxA in LN... This work, however, did not reveal a mechanism of IFN I resolution... Most species have one to three Mx protein isoforms with different antiviral activity depending on their intracellular localization... Mouse Mx1 protein is found primarily in the nucleus whereas human MxA is cytoplasmic... Human MxA can be induced by IFN or directly by the virus through different pathways... As mentioned previously, in contrast to non-natural hosts, natural SIV hosts downregulate MxA responses during the transition to chronic infection despite high viremia... Additionally, the virus may synergize with IFN to increase Mx levels... Studying variations in the Mx genes, simultaneously with standardized screening of their antiviral properties in natural and non-natural SIV hosts, could explain why natural hosts can downregulate MxA responses with the onset of the chronic stage of infection... Evidence supporting a role for MxA genes, warrants studying polymorphisms in MxA genes, which may shed light on the mechanism of active IFN downregulation.

No MeSH data available.


Related in: MedlinePlus