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We will be provided with an authorization token (please note: passwords are not shared with us) and will sync your accounts for you. Human immunodeficiency virus type 1 (HIV-1) infects humans and chimpanzees but not old world monkeys (OWMs) such as the rhesus monkey (Rh) and cynomolgus monkey (CM).
Human immunodeficiency virus type 1 (HIV-1) is a causative agent of acquired immunodeficiency syndrome (AIDS). Human immunodeficiency virus type 1 belongs to the family Retroviridae, subfamily Lentivirus. Many trials of small animal models for HIV-1 infection have failed due to lack of host factors in mice, which are necessary for efficient virus replication (Figure 1). Human immunodeficiency virus type 1 pre-integration complex (PIC) containing viral cDNA and viral IN are translocated into the nucleus.
Amino acid sequences of CD4, CXCR4, CCR5, CycT1, and CRM1 in Old World monkeys (OWMs) are almost identical to those of the human orthologs, while New World monkeys, such as common marmosets and squirrel monkeys, have less functional CD4 and CCR5 receptors (LaBonte et al., 2002). The PRYSPRY domain is specific for the α-isoform among at least three splicing variants transcribed from the TRIM5 gene.
Simian immunodeficiency virus isolated from sooty mangabey (SIVsm) and SIV isolated from African green monkey (SIVagm) replicate in their natural hosts (VandeWoude and Apetrei, 2006) and CD4+ human cells. Human immunodeficiency virus type 2 (HIV-2) is assumed to have originated from SIVsm as a result of zoonotic events involving monkeys and humans (Hahn et al., 2000).
Tripartite motif 5α is thought to recognize viral cores through its PRYSPRY domain. Soyez egalement charitables en desactivant vos bloqueurs de pub, ce site n'est finance que par ses annonceurs et pourrait cesser son activite si ces derniers ne sont plus affiches.
If you could have written a song about how you felt after your most recent breakup, whether you broke up a week or several years ago, what would you say? Viruses have played an important role in human evolution and have evolved diverse strategies to co-exist with their hosts.
Apart from attachment of the virus particle to the host cell, viral replication itself frequently elicits stress responses, such as ER stress or production of reactive oxygen species (ROS) that induce autophagy [47]. Conflicting reports have been published as to the role of autophagy for the HCV replication cycle [23,26,79,80].
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This page doesn't support Internet Explorer 6, 7 and 8.Please upgrade your browser or activate Google Chrome Frame to improve your experience. HIV-1 efficiently enters cells of OWMs but encounters a block before reverse transcription. CD4, the cellular receptor for HIV-1, was first identified as a host range barrier because mouse CD4 does not bind to HIV-1 envelope protein (Landau et al., 1988). HIV-1 non-structural proteins, Tat, Rev, and Nef, are early gene products produced from multiply spliced mRNAs (Feinberg et al., 1986).
To determine further details regarding the interaction between CA and TRIM5α, biochemical and structural analyses of the PRYSPRY domain, especially the V1 loop bound with CA, are required. Due to spammers, your comment will not appear until it has been cleared by a website editor.
As obligate intracellular pathogens, viruses exploit and manipulate different host cell processes, including cellular trafficking, metabolism and immunity-related functions, for their own survival. IntroductionTo co-exist with their hosts viruses have evolved diverse mechanisms to exploit cellular processes and to evade from host defenses. Impact of Viral Infection on AutophagyAutophagy induction involves the coordinated action of several key factors (Figure 1). Viruses can either induce (green arrows) or inhibit the autophagy pathway (red studded lines). Interplay Between Toll-like Receptors (TLRs) and Autophagy During Viral InfectionThe innate immune system is considered as the first line of defense against invading pathogens like viruses and bacteria. For instance, Sir and co-workers used the highly permissive cell clone Huh 7.5 and found that transfection of HCV RNA induces autophagic vacuoles and leads to an incomplete autophagic process that promotes viral replication [23]. No point in taking medicine everyday when u won't get cure from it and I was advice to seek for natural herbal cure, after some time I found dr fara is the most trustful herbalist that have herbs to cure wicked symptom's,I emailed dr fara,he told me what is needed for him to cure me which i did , I only used his natural herbs for two weeks it was 100% cure.
Nevertheless, the host range of HIV-1 is extremely narrow, being limited to humans and chimpanzees (Gao et al., 1999). Human CD4 transgenic mice, however, were not susceptible to HIV-1 infection (Lores et al., 1992). The RING, B-box2, Coiled-coil, PRYSPRY, or CypA domains of Rh-TRIM5α and TRIMCyp are shown by squares.
The PPYSPRY domain is thought to recognize viral cores, as TRIM5α lacking this domain does not show antiviral activity.
The ribbons represent the backbone of HIV-2 capsid proteins, and seven α-helices are labeled. The structures of the N-terminal domain of GH123 are shown, and seven color-coded α-helices are labeled.
In this article, we review evidence for how autophagy, a highly conserved cellular degradative pathway, serves either as an antiviral defense mechanism or, alternatively, as a pro-viral process during virus infection. The inner autophagosomal membrane and cargo is degraded by acid hydrolases inside the autolysosome, and recycling of the resulting macromolecules is mediated via permeases. Viral induction of autophagy can be achieved during viral entry via interaction with cell surface receptors, via interaction with stress sensors or during viral replication. An accumulation of misfolded or unfolded proteins in this compartment results in ER stress and activates an unfolded protein response (UPR) mediated by three ER membrane-associated proteins: PERK (PKR-like eIF2? kinase), ATF6 (activating transcription factor-6) and IRE1 (inositol requiring enzyme 1).
Autophagy selectively transfers viral nucleic acids to endosomal compartments to stimulate innate immune responses via TLRs.
Upon viral infection, many cytosolic and endosomal immune sensors detect different components of viral nucleic acids to elicit an innate immune response. Autophagosomes have been proposed provide a membrane platform for viral replication complexes or to mediate virus assembly and release. Dreux and co-workers employed Huh7 cells infected with HCV and found that autophagy was only required for initiating the translation of incoming viral RNA, but not for establishment or maintenance of viral replication [26]. This narrow host range has hampered the establishment improved animal models of HIV-1 infection that are needed to facilitate the development of an efficacious vaccine against HIV-1 infection. The virus RNA genome is subsequently reverse transcribed by viral-associated reverse transcriptase and resultant double-strand cDNA is transported to the nucleus. LEDGF interacts with HIV-1 IN and is thought to guide PIC toward sites of active transcription for integration of viral cDNA into the human chromosome. Importantly, resistance against HIV-1 infection was shown to be dominant in heterokaryons between human and OWM cells, suggesting the presence of inhibitory factor(s) against HIV-1 infection but not for simian immunodeficiency virus (SIV) in OWM cells (Munk et al., 2002).
TRIM5α is thus thought to use both proteasome-dependent and -independent pathways to restrict HIV-1. Blue and red wireframes denote side chains of glutamic acid at the 97th (D97) and arginine at the 119th (R119) positions, respectively.
It is not yet clear whether monkey TRIM5α does or does not recognize HIV-1 CA with endogenous CypA.
Furthermore, we highlight recent reports concerning the role of selective autophagy in virus infection and how viruses manipulate autophagy to evade lysosomal capture and degradation. In contrast to proteasomal degradation that specifically targets ubiquitinated proteins, autophagy is mediated by the lysosome, which serves as an end point degradative organelle. In principle, any of the above mentioned Atg8 family proteins can serve as a marker of autophagosomes in mammalian cells, however, conventionally only MAP1LC3B (referred to as LC3 henceforth) is used as marker of autophagosomes in mammalian cells [16,17].
Viruses also inhibit autophagy at early or late stages of the pathway, during initiation or maturation, respectively.
Furthermore, autophagy can selectively target viral components and degrade them in lysosomes.
There are three classes of PRRs or immune sensors: Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs) [52]. Furthermore, viruses can trigger selective autophagy to degrade either lipids (lipid droplets) for energy production during viral replication or to subvert immune responses by selectively degrading key regulatory molecules. Moreover, in Huh7 cells containing HCV replicons of different genotypes (1a, 1b or 2a), the knock down of Atg proteins did not affect expression of viral proteins [81]. TRIM5α is one of splicing variants produced by TRIM5 gene and TRIM5 proteins are members of the TRIM family containing RING, B-box 2, and coiled-coil domains.
In the nucleus, viral-associated integrase (IN) inserts viral cDNA into the human chromosome. The numbers in parentheses show the amino acid positions counting from the initiation methionine codon of the CypA open reading frame. The distinct molecular mechanism of the proteasome-independent pathway has yet to be elucidated. Autophagy is thus a catabolic process that maintains cellular homeostasis by degradative removal of damaged or excess cellular organelles and protein aggregates from the cytoplasm, thereby enabling cell survival. During autophagosome formation and elongation, the cytosolic LC3, termed LC3-I, is proteolytically cleaved and coupled to phosphatidyl-ethanolamine (PE) to form LC3-II, which is inserted into the autophagosomal membrane [1,9]. When ER stress is triggered, Bip interacts with unfolded luminal proteins, thus leading to the release of PERK, IRE1 and ATF6. Lastly, autophagy mediates the delivery of viral antigens to MHC-I and -II complexes to allow antigen presentation. The mechanistic details related to proviral functions of autophagy are discussed in the text.
In contrast, in another study that employed Huh7.5 cells, the knock-down of Atg7 dramatically decreased production of HCV particles, but did not affect viral replication [80].

The transcription is enhanced by cellular activation and mRNA and full-length viral genome RNA are exported from the nucleus.
TNPO3 also binds to IN, but it is also thought to associate with viral capsid (CA) protein and supports nuclear translocation of PICs. Although the precise three-dimensional crystal structure of the PRYSPRY domain has not been resolved, TRIM5-21R assembled and formed two-dimensional paracrystalline hexagonal arrays in vitro (Ganser-Pornillos et al., 2011). Both cell culture and in vivo studies revealed the fundamental roles of autophagy in numerous diseases, including cancer or neurodegeneration, in aging, but also in innate and adaptive immunity to pathogen infection.In general, autophagy can be broadly classified as macroautophagy, microautophagy and chaperone-mediated autophagy (CMA). The two main characteristics of autophagy detection is, first, the increase in intracellular levels of LC3-II and, second, the re-localization of evenly distributed cytosolic LC3-I into LC3-II positive punctuate structures, representing autophagosomes [1,9]. PERK mediates the phosphorylation of eukaryotic translation initiation factor 2 ? (eIF2?), resulting in rapid reduction of mRNA translation, thereby reducing the load of new proteins in the ER [48]. Moreover, a recent report showed that knock-down of the autophagy-related proteins beclin 1 (BCN1) and Atg7 inhibited HCV replication in immortalized human hepatocytes (IHHs) [82]. During the first year,I had faith in God that i would be healed someday.This disease started circulating all over my body and i have been taking treatment from my doctor, few weeks ago i came on search on the internet if i could get any information concerning the prevention of this disease, on my search i saw a testimony of someone who has been healed from (Hepatitis B and Cancer) by this Man Dr OMOYE and she also gave the email address of this man and advise we should contact him for any sickness that he would be of help, so i wrote to Dr. Viral proteins assemble beneath the plasma membrane and virus particles bud from plasma membrane (Figure 1). It is currently unclear whether mouse orthologs of either or both of these factors are defective in nuclear transport and integration of HIV-1. Human but not mouse CycT1 binds to Tat and activates transcription from HIV-1 LTR (Garber et al., 1998). It is therefore likely that direct binding of Rh-TRIM5α proteins to incoming HIV-1 CA proteins causes CA disassembly, which is observed as proteasome-independent restriction. This result is consistent with the observation of RING-proteasome dependency of SIVmac239 restriction by TRIM5α.
All three pathways share the same mode of degradation via the lysosome, but are mechanistically distinct from each other [1].
Indeed, infections with a wide range of DNA or RNA viruses increase abundance of autophagosomes or autophagic vesicles in infected cells [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34].
In addition, PERK phosphorylation of eIF2? allows the translation of activating transcription factor 4 (ATF4) to induce transcription of genes involved in amino acid synthesis and apoptosis [48]. OMOYE telling him about my (HERPES Virus) he told me not to worry that i was going to be cured!! Previous studies have shown that sequence variation in variable regions of the PRYSPRY domain among different monkey species affects species-specific retrovirus infection, while amino acid sequence differences in the viral capsid protein determine viral sensitivity to restriction.
Nevertheless, triple-transduction of mouse cells with human CD4, CXCR4, and CycT1 was insufficient to induce productive viral infection (Bieniasz and Cullen, 2000). However, the hexagonal lattices of HIV-1 CA that mimic the surface of core act as template for stabilization of TRIM5-21R arrays in a PRYSPRY-dependent manner (Ganser-Pornillos et al., 2011). Microautophagy, mainly characterized in yeast [2], involves a direct engulfment of the cytoplasm at the lysosomal membrane, facilitated by protrusion of arm-like structures, and CMA specifically directs translocation of unfolded proteins with an inherent consensus motif (KFERQ) across the limiting membrane of the lysosome for degradation [1].
Furthermore, several electron microscopy-based studies revealed the presence of double-membrane structures that are characteristic of autophagosomes. IRE1 is autophosphorylated to function as an endoribonuclease, responsible for the unconventional splicing of the X box-binding protein 1 (XBP1) mRNA.
Many RNA viruses release their viral RNA genome into the cytoplasm to establish sites of RNA replication, thus allowing cytosolic PRRs to be activated [53]. In fact, a recent study highlighted the importance of the UPR and autophagy during HCV infection and demonstrated that autophagy enhances HCV replication by inhibiting an innate immune response [36].
TRIM5α recognizes the multimerized capsid proteins (viral core) of an incoming virus by its PRYSPRY domain and is thus believed to control retroviral infection. SIVagm, simian immunodeficiency virus isolated from an African green monkey (Song et al., 2005b). Furthermore, a crucial component for CMA is the lysosomal membrane receptor, lysosome-associated membrane protein (LAMP) type 2A [1]. However, it is important to note that increased amounts of autophagosomes in infected cells can either be due to their enhanced formation or to their accumulation due to a block in their maturation or degradation. The resulting translation product XBP1 regulates transcription of genes encoding for ER chaperones, biogenesis of phospholipids and components of the ER-associated protein degradation (ERAD) machinery. However, activation of endosomal TLRs can be limited, because viral RNA is packed into the nucleocapsid or sequestered in membrane-associated replication complexes and thus, well protected from the endosomal environment. Since Huh7 clones differ in their capability to mount an innate antiviral defense, the use of different cell lines could explain, at least in part, the contradictory results.More recently, Sir et al proposed a direct role of autophagy in serving as platforms for viral RNA replication [79]. Oh is by this time last year I start feeling bad about my life, I feel pain everyday of my life but am very happy now that am really cured I couldna€™t have done this on my own. CRM1, a nuclear export factor that functions in association with Rev, has been suggested to be one of the late-phase factors important for the export of unspliced full-length viral genome from the nucleus (Zheng et al., 2003).
Therefore, to understand the reason for increased autophagosome numbers in virus-infected cells, it is important to study the impact of viral infection on autophagic activity or autophagic flux, which is defined as the measurement of the balance between the rate of autophagosome formation and degradation. Finally, activated ATF6 translocates from the ER to the Golgi to undergo cleavage by regulated intramembrane proteolysis (RIP) by site 1 and site 2 proteases. Nonetheless, TLRs frequently trigger an immune response targeting a number of viral infections via poorly defined mechanisms [54]. In this study, the authors describe the localization of HCV replicase proteins NS5A and NS5B as well as nascent HCV RNA to autophagosome-like structures. I was searching the internet about this sickness last months when I found about great Dr AZIZA, the man that kept his words. It has also been reported that some Rh and CM individuals have retrotransposed cyclophilin A open reading frame in the TRIM5 gene, which produces TRIM5–cyclophilin A fusion protein (TRIMCyp). Further studies are necessary to identify host cellular factors that are necessary for virus replication in humans but defective in mouse cells in order to establish small animal models of HIV-1 infection. Assays to measure autophagic activity in mammalian cells have been described in detail in other reviews and, therefore, will only be mentioned here [16,17]. The cytoplasmic domain of ATF6 functions as a transcription factor to transactivate genes encoding ER chaperones, ERAD components and protein foldases [48]. The first report demonstrating that autophagy can be involved in delivering PAMPs or viral nucleic acids to endosomal TLRs comes from the study of VSV-infected plasmacytoid dendritic cells (pDCs) [55] (Figure 3). However, these data are in direct opposition to studies showing that HCV proteins do not colocalize with autophagosomes in infected cells [23,49,80]. I wrote Dr AZIZA 's email about my problem, immediately I got a reply from him asking me to fill a form which I immediately did and send back to him, after some minutes he reply me that he have work on my cure that I need to provide some materials which can enable him to work on my cure which I did on the next day of it, after some hours he inform me that he has gotten the things needed for the preparation of the herbal medication that will cure my GENITAL HERPES VIRUS.
TRIMCyp, which was originally identified as an anti-HIV-1 factor of New World owl monkeys, is an interesting example of the gain of a new function by retrotransposition. Among these, PERK and ATF6 function as inducers of autophagy, while IRE1 acts as a negative regulator [47]. The authors showed that the production of interferon-? (IFN-?) by VSV-infected pDCs depended on the autophagic delivery of viral replication intermediates to TLR7 present on late endosomes. Thus, although autophagy is required for HCV replication, the precise role of autophagy or autophagy-related proteins in viral replication remains to be determined.In the case of coronaviruses, autophagosomes were initially proposed to be sites of RNA replication, since viral replicase proteins colocalized with LC3 and the deletion of Atg5 restricted viral replication [83].
After he finish preparing the medication, he send it to me and also gave me instructions on how i will be taking the medication. As different TRIM5 genotypes of Rh showed different levels of simian immunodeficiency virus replication in vivo, the TRIM5 genotyping is thought to be important in acquired immunodeficiency syndrome monkey models.
It was recently shown that HCV infection can induce ER stress and activate all three sensors of UPR [47].
However, subsequent studies suggested that the role of autophagy in viral replication might be a cell type-specific effect [84]. These yeast-specific Atgs provided great insight into the molecular aspects of autophagy in higher eukaryotes. Induction and Inhibition of Autophagy by VirusesVarious studies reported the activation of autophagy upon virus infection as inferred from the increased number of autophagic vesicles, the monitoring of LC3-I to LC3-II conversion and the elevated number of LC3-positive punctae in infected cells [21,22,23,29,30,32,33,35]. Furthermore, upon treatment of VSV-infected pDCs with Wortmannin or 3-methyladenine (3-MA) that both inhibit Vps34 activity, IFN-? production was blocked.
Electron tomography and 3D reconstructions of coronavirus-infected cells demonstrated that DMVs form an adjoining network likely derived from the ER [85]. Moreover, the first identified mammalian Atgs, Atg5 and Atg12, were shown to be highly homologous to those in yeast [1]. However, considering the dynamic nature of autophagy, it is important to determine the rate of autophagic flux to gain mechanistic insight into how viral infection affects autophagic activity in cells. The exact mechanism by which HCV mediates induction of autophagy via ER stress and UPR remains to be investigated.
Moreover, LC3 was localized to the viral replicase machinery, and surprisingly, only unlipidated LC3-I, but not LC3-II, decorated the replication machinery, as well as replication membranes [86].
In fact, recent reports demonstrated that Sindbis virus and hepatitis C virus (HCV) infection increase autophagic flux [36,37].
In contrast, a very recent study by Mohl et al provided evidence that HCV-induced autophagy is independent of UPR [49]. However, the exact mechanism by which viral PAMPs are selectively targeted by autophagosomes to the TLR-resident late endosomal compartment remains to be determined.The involvement of autophagy in delivering viral PAMPs to endosomal PRRs is also conserved in non-immune cells. Furthermore, viral DMVs also stained positive for ER-associated degradation (ERAD) markers. My name is Ary Rojas i was herpes positive for years and came across some post of a doctor call okoh and the good jobs on how he has cure people who was also HERPES positive and now they are now negative.I contacted this doctor about my problem with herpes, he assured me of a cure and i trusted him on it which he sent to me.
The majority of proteins involved in the autophagy machinery are required for formation and elongation of the phagophore [1] (Figure 1). Infection of mouse embryonic fibroblasts (MEFs) expressing GFP-LC3 with Sindbis virus resulted in an increase in the percentage of cells containing GFP-LC3 positive dots concomitant with an increase in LC3-II abundance.

Subgenomic replicons expressing nonstructural (NS3-5B) proteins, as well as a mutant virus lacking the envelope glycoproteins, potently induced autophagy in the absence of detectable UPR [49]. Studies with Coxsackie virus B3 (CVB3)-infected kidney fibroblasts demonstrated autophagy-dependent activation of TLR3 [56]. This data suggests that coronaviruses do not require autophagosomes, per se, but utilize components of the autophagy pathway.
In addition, infected cells contained reduced levels of p62 (an accepted marker of autophagic flux), with no significant changes of its mRNA amounts, indicating a complete autophagic response during virus infection [37]. Thus, taking both studies together [36,49], it is unclear how autophagy is induced in HCV infection. The same study revealed that TLR3-decorated vesicles colocalized with LC3-positive structures and that the activation of TLR3 via poly (I:C) or CVB3 infection was sensitive to inhibitors of autophagy induction, autolysosomal acidification and lysosomal proteases. The reason why most people are finding it difficult to cure HERPES is because they believe there is no cure for it but with doctor okoh medication which can easily get rid and totally cure the symptoms of HERPES in the body which I'm also a living testimony that doctor okoh can cure HERPES VIRUS. Non-selective or starvation-induced autophagy is thought to play an important role in supplying energy to the cell by the bulk degradation of proteins and organelles, whereas selective autophagy involves the recruitment of specific adaptor proteins such as p62, NBR1 (neighbor of BRCA1 gene 1), BNIP3 (BCL2 and adenovirus E1B 19 kDa-interacting protein 3) and NIX (NIP3-like protein X) that recognize ubiquitinated protein complexes and organelles, such as mitochondria (mitophagy), peroxisomes (pexophagy) and ribosomes (ribophagy), to target them to autophagosomes for degradation [10,11,12]. In case of HCV infection, a study by Ke and Chen [36] demonstrated that despite unaltered levels of p62 in infected cells, LC3-II protein levels were increased upon treatment with lysosomal protease inhibitors (E64 and pepstatin A), or chloroquine (a vacuolar ATPase inhibitor) or bafilomycin A1 (an inhibitor of lysosomal acidification), [36] arguing that HCV does not block autophagy. Recent studies with other related flaviviruses, such as Dengue virus (DENV) and Modoc virus, showed that virus infection induced autophagy [50]. Furthermore, even in the absence of poly (I:C) or CVB3 infection, TLR3 still localized to LC3-positive structures, arguing that even under basal conditions, the autophagosome might fuse with TLR3-positive endosomal vesicles [56].
It was found that the viral protein NS4P, a marker of rotavirus replication sites, colocalized with LC3-positive structures [19] (Figure 4).
More recently, studies have shown that selective autophagy plays a crucial role in the elimination of pathogenic bacteria and viruses, termed xenophagy, thus extending the functions of autophagy to innate and adaptive immunity against pathogens [11]. In line with this conclusion, the authors showed that treatment of infected cells with chloroquine and bafilomycin A1 resulted in increased LC3-II levels in HCV infected cells as compared to uninfected cells, clearly indicating enhanced autophagic flux. In fact, expression of the replicase protein NS4A from either virus was sufficient for autophagy induction via UPR [50] (Figure 2). The resulting ‘mixed’ compartments might therefore serve as antiviral platforms specialized in sensing viral PAMPs and eventually triggering downstream signaling events.Induction of autophagy can also occur via direct activation of TLRs [57]. These structures did not stain positive for lamp1, suggesting a block in fusion of virus-associated autophagic structures with lysosomal compartments [19].
Moreover, studies on selective autophagy have underlined the relevance of post-translational modifications, such as phosphorylation and ubiquitination, in linking autophagy adaptor protein function to autophagy substrate recognition [13,14]. In addition, by employing a tandem-LC3 reporter (mRFP-GFP-LC3), a tool to analyze both autophagosome and autolysosome formation, the authors found that HCV induced autophagosomes that matured into autolysosomes, thus revealing a complete autophagic response in HCV-infected cells. However, the role of adaptor proteins in non-selective autophagy still remains to be fully determined.In this review we will discuss the current understanding of how virus infection regulates the crosstalk between intracellular signaling and autophagy.
In contrast, an earlier study by Sir and co-workers proposed that autophagy is incomplete, and cells transfected with HCV RNA formed autophagosomes that, due to inefficient fusion with lysosomes, did not convert into autolysosomes [23]. Apart from a direct contribution to the formation of membranous replication factories, autophagy can promote viral replication in other ways. Furthermore, we will highlight recent reports on how autophagy exerts its antiviral function and the countermeasures adopted by viruses to exploit and subvert autophagy.
In the case of varicella-zoster virus (VZV) infection, it was demonstrated that virus-induced ER stress and UPR response precede autophagosome formation [51].
Upon TLR activation, MyD88 and TRIF directly interact with Beclin-1 leading to the formation of Beclin-1-Vsp34 complexes that induce autophagy [59].The role of autophagy in delivering viral PAMPs to TLRs and the subsequent induction of autophagy upon TLR activation indicates the existence of a positive feedback loop. For instance, a recent study by Heaton and co-workers identified a novel proviral mechanism of autophagy: the production of energy [87].
For instance, Kaposi’s Sarcoma herpesvirus (KSHV), murine ?-herpesvirus 68 (MHV68) and Herpes Simplex virus 1 (HSV-1) target Beclin-1, thereby inhibiting autophagosome formation. The authors show that ER stress upon VZV infection is due to abundant VZV glycoprotein biosynthesis, which in turn triggers to UPR and thus, autophagy to maintain cellular homeostasis. This feedback loop might not only play an important role in the autophagic sequestration and delivery of PAMPs to endosomal compartments, but also serve for autolysosomal degradation of virions and viral proteins, as well as for antigen presentation via MHC-I and MHC-II molecules, thereby triggering the adaptive immune response.
These viruses encode proteins that competitively bind to Beclin-1 and thus inhibit its interaction with Vps34. KSHV encodes a viral Bcl-2 homologue, which binds Beclin-1 with much higher affinity than cellular Bcl-2, thereby preventing incorporation of Beclin-1 into Vsp34 complexes [38]. M11, the viral Bcl-2 homologue encoded by MHV68, also interacts with Beclin-1 and inhibits autophagosome formation [39]. In the case of HSV-1, the virally encoded protein ICP34.5 interacts with Beclin-1 via a 20 amino acid residues-long region (aa 68-87) to inhibit autophagosome biogenesis [40]. Interestingly, deletion of ICP34.5 leads to accumulation of HSV-1 particles in autophagosome-like structures, which can be visualized by electron microscopy [41]. Other viruse,s such as human immunodeficiency virus-1 (HIV-1), influenza A virus (FluAv), coxsackievirus B3 (CVB3) and poliovirus inhibit autophagy by blocking autophagosome maturation or degradation.
In the case of HIV-1 and FluAv, the viral proteins Nef and M2, respectively, block autophagosome maturation by a still poorly defined mechanism that depends on their interaction with Beclin-1 [27,28]. Antiviral Functions of AutophagyAs an organelle gathering cytosolic content into a double-membrane vesicle that fuses with endosomal compartments, the autophagosome can specifically deliver intracellular pathogen-associated molecular patterns (PAMPs) to endosomal pattern recognition receptors (PRRs) and MHC-loading compartments to initiate innate and adaptive immune responses (Figure 3). Studies with CVB3 and poliovirus show that autophagy is inhibited at the stage of autolysosomal degradation [18]. Moreover, the autophagosome can selectively target virions and virus components for degradation via the autolysosome. Moreover, in the case of coxsackievirus B3 (CVB3) [25,42], it was demonstrated that protein levels of LC3-II and p62 increase over time, suggesting that viral infection leads to an accumulation of autophagosomes due to a block in autolysosomal degradation [25,42]. However, it remains to be determined how these viruses specifically target autolysosomal degradation.
Role of Autophagy in Antigen PresentationThe role of autophagy is not limited to the innate immune response, but also plays a major role in the adaptive immune response by processing and delivering antigens for presentation in complex with MHC-I and MHC-II molecules [63] (Figure 3).
Typically, MHC-I molecules present endogenous antigens that are degraded by the proteasome and transported into the ER, where they are loaded onto MHC-I molecules. After transport to the cell surface, peptide-loaded MHC-I stimulates a CD8+ T-cell response responsible for controlling infections [64].
MHC-II molecules present exogenous antigenic peptides that are processed by lysosomal degradation. Peptides are loaded onto MHC-II and transported to the cell surface to stimulate a CD4+ T- cell response [64]. Notably, exogenous antigens can also be presented on MHC-I molecules to mediate a CD8+ T-cell response by a mechanism termed “cross-presentation” [65]. This is found primarily with dendritic cells, macrophages and B lymphocytes and plays a major role in the immune defense against numerous viral and bacterial infections.A number of studies have convincingly demonstrated that autophagy can influence the presentation of viral antigens on MHC-I and MHC-II [66]. Studies with HSV-1 showed that at early time points after infection, autophagy is not required for viral antigen processing and presentation of MHC-I peptides, but comes into play at late stage of infection [67]. However, it remains unknown how degradation of HSV-1 particles by the autophagosome results in the presentation of viral antigens to ER localized MHC-I molecules. In the case of Epstein Barr virus (EBV), the viral protein EBNA1 is targeted to MHC-II compartments via autophagic uptake and fusion of autophagosomes with these compartments [68]. Inhibition of autolysosomal acidification resulted in enrichment of EBNA1-positive autophagosomes, and knock-down of Atg12 rendered the cells unable to stimulate MHC-II-dependent activation of T-cells [69].
Importantly, already under normal conditions and in the absence of viral infection, autophagy was required for the consecutive delivery of antigens to MHC-II molecules, arguing for a crucial role of autophagy in MHC-II presentation of antigens in vivo [70].
Furthermore, by fusing the matrix protein of influenza virus to LC3, an increased MHC-II activation of CD4+ T-cells was observed, thus revealing an unexplored strategy for vaccine development [70].
Role of Autophagy in Promoting Viral ReplicationMost positive-strand RNA viruses re-shape the endomembrane system in order to create membrane-associated replication ‘factories’ [71]. This reorganization of intracellular membranes frequently requires autophagy and was first described for the poliovirus [72]. By using thin section EM analysis of infected cells, double-membrane vesicles (DMVs) were detected that are characteristic of autophagosome-like structures (Figure 4). These structures stained positive for the viral protein 2BC, and they did not co-fractionate with markers of other known organelles, highlighting their distinct nature [72]. Expression of the viral proteins 2BC and 3A resulted in the lipidation of LC3 and induced the formation of autophagosome-like DMVs [72]. These properties are not unique for poliovirus, but have been found for several other picornaviruses such as CVB3, enterovirus 71 (EV71) and foot-and-mouth disease virus (FMDV) [42,73,74].
Cells infected with these viruses also contain accumulations of DMVs that are not only morphologically similar, but also contain LC3 as well as viral replicase proteins (Figure 4). However, it is important to note that the membrane composition of picornaviral replication sites is heterogeneous, and other mechanisms have been suggested to explain their formation and composition [75,76]. Importantly, key elements of the secretory pathway are involved in the biogenesis of these membranous structures, including COP-II coated vesicles, Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor-1 (GBF-1), ADP-ribosylation factor 1 (ARF1) and phosphatidylinositol 4-kinase III beta (PI4KIII?) [77]. Finally, it was also shown that poliovirus, EV71 and FMDV can replicate in the absence of autophagy, although in some cases virus production was decreased [18,42,73,78]. These studies suggest that autophagosomes, per se, are dispensable for the biogenesis of viral replication sites, although some autophagy proteins can contribute to their morphological heterogeneity.

Background information on herpes
Virus gastroenteritis treatment

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