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Roles of Endogenous Retroviruses in Cancer and Auto-immune Diseases

内源性逆转录病毒在癌症和自身免疫性疾病中的作用

基本信息

批准号：
9354874
负责人：
LEONARD EVANS
金额：
$ 25.83万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9354874
关键词：
3T3 Cells APOCEC3G gene Cell Line Cells Cytidine Cytidine Deaminase Deamination Defect Derivation procedure Development Disease Elements Embryonic Development Endogenous Retroviruses Engineering Event Evolution Exclusion Exhibits Friend Murine Leukemia Virus Friends Generations Genes Genetic Recombination Genome Genomics Goals HIV Harvest Homologous Gene Host Defense Human Immune System Diseases In Vitro Inbred Strains Mice Infection Intracisternal A-Particle Elements Knockout Mice Length Lupus Nephritis Malignant Neoplasms Methionine Mouse Mammary Tumor Virus Mouse Strains Murine leukemia virus Mus Mutation NFS/N Mouse NIH 3T3 Cells Pathologic Processes Physiological Physiological Processes Placenta Play Polymerase Polyproteins Population Process Proteins Proviruses Recombinants Reporting Retroviridae Retroviridae Infections Role Site Transcript Transcriptional Regulation Translations Viral Viral Genome Viral Load result Viral Physiology Virion Virus Virus Replication Wild Type Mouse gag Gene Products in vivo insight mouse model nervous system disorder novel receptor trophoblast

项目摘要

It is estimated that humans as well as mice have acquired approximately 40,000 copies of retroviruses over the course of evolution such that approximately 8% of their genomic sequences are retroviral in origin. The majority of these retroviruses are no longer full length and do not encode functional retroviruses. However, several endogenous retroviral elements function in important physiological roles such as transcriptional regulation of host genes or the induction of placenta-trophoblast fusion during embryogenesis. In humans, the HERV-K (HLM-2) group of endogenous retroviruses are the most recently acquired and are polymorphic in the population. The expression of these viruses have been associated with a number of diseases but have yet to be established as causative. A group of endogenous retroviruses of mice, termed the polytropic viruses, like the HERV-K (HLM-2), are the most recently acquired endogenous retroviruses in mice. They are polymorphic among mouse strains and are associated with a number of pathogenic processes. Upon infection of susceptible mice by ecotropic murine leukemia viruses (MuLVs) endogenous polytropic transcripts can recombine with incoming ecotropic murine leukemia viruses. This results in the generation of replication-competent polytropic MuLVs that utilize a different cellular receptor for entry and exhibit an altered host range. The generation of recombinant polytropic MuLVs is associated with the development of fatal proliferative diseases. Furthermore, some recombinant polytropic viruses induce severe neurological diseases, and the expression of endogenous polytropic envelope sequences in certain mouse strains correlates with the development of murine lupus nephritis, a severe immunological disorder. Although the endogenous polytropic proviruses are transcribed; replication of the endogenous polytropic viruses in the absence of recombination has not been observed. This may reflect defects in the endogenous viral genome but may also be influenced by the activity of various restriction factors. The fact that exogenous MuLVs are capable of replicating in mice indicates that they have evolved mechanisms to circumvent the activity of at least some of the restriction factors such as the murine APOBEC3 (mA3). Thus, exogenous retroviruses might facilitate, through complementation, active replication of endogenous retroviruses. We have shown in mice infected with the exogenous ecotropic Friend MuLV (F-MuLV) that endogenous polytropic transcripts not only recombine with F-MuLV but are mobilized by packaging of complete transcripts within F-MuLV virions in the absence of recombination. These pseudotyped endogenous polytropic transcripts, consisting of severely deleted as well as nearly complete genomes, are transferred by infection and integration into the genome of new cells. The newly infected cells are also infected by F-MuLV which enables the packaging and release of infectious progeny virions containing genomes transcribed from the newly integrated defective mobilized proviruses. More recently we demonstrated the mobilization of endogenous polytropic genomes from F-MuLV-infected NFS/N mice as early as one day after infection corresponding to a single replication cycle. Thereafter, the level of mobilized viruses increased throughout the course of disease and remained a major component of the viral load. The mobilized viruses identified were limited to endogenous polytropic proviral transcripts at the exclusion of other endogenous retroviral elements such as intracisternal-A particles (IAPs) or mouse mammary tumor viruses. The endogenous polytropic proviruses are comprised of two structural subclasses termed Polytropic (PT) and Modified Polytropic (mPT). We observed a distinct shift in the subclass of proviruses from the mPT subclass to the PT subclass of polytropic proviruses detected during the course of infection. Studies conducted in 2016 further characterized the mobilized polytropic proviruses. Some of the mobilized proviruses exhibited nearly identical sequences to proviruses identified in the mouse genomic reference sequence. Others exhibited definitive evidence of recombination events that occurred prior to the derivation of inbred mouse strains. Furthermore, some of the endogenous proviruses exhibit identical lethal mutations strongly suggesting that they entered the germline as defective passengers of infectious viruses through mobilization. The mobilization of intact endogenous retroviruses is unprecedented and may have important implications for the involvement of endogenous retroviruses in disease processes. Further, mobilization of proviruses may have played an important role in the acquisition of endogenous proviruses during evolution. Exogenous mouse retroviruses encode a glycosylated gag protein (gGag) originating from an alternate translation start site upstream of the methionine site of the gag structural polyproteins. Mutations that eliminate the synthesis of gGag impede in vivo replication of the virus with little effect on replication in fibroblastic cell lines. APOBEC3 proteins have evolved as innate defenses against retroviral infections. Both mice and humans express APOBEC3 proteins that have cytidine deaminase activity leading to hypermutation of viral transcripts and inactivation of infecting retroviruses. HIV encodes the VIF protein to evade human APOBEC3G (hA3G), however mouse retroviruses do not encode a VIF homologue and it has not been understood how they evade mouse APOBEC3 (mA3). We have found that a mouse retrovirus utilizes the gGag protein to evade APOBEC3. gGag is critical for infection of in vitro cell lines in the presence of APOBEC3. Furthermore, a gGag-deficient virus restricted for replication in wild-type mice replicates efficiently in APOBEC3 knockout mice implicating a novel role of gGag in circumventing the action of APOBEC3 in vivo. We have found that mA3 packaged at very high levels in wild-type virions results in a loss of specific infectivity and a loss in the specific enzymatic activity of the viral polymerase. This is accompanied by a substantial increase in the overall mutation rate. However we did not observe G to A hypermutation in either the wild-type or gGag-deficient MuLVs. Thus, the inhibitory action of mA3 on the MuLVs is unlikely to involve cytidine deamination. It has been reported by one group that the ecotropic MuLV, AKV, in contrast to other MuLVs, undergoes G to A hypermutation when mA3 is packaged within AKV virions in human 293T cells. We have found that hypermutation of AKV occurs in mouse 3T3 cells in the absence of detectable mA3. Furthermore, hypermutation occurs in only a portion of the virus transcripts suggesting that a restriction factor is present in only a portion of the virions. Identical results were observed in NIH 3T3 cells that were engineered to express mA3, indicating that its expression did not augment the mutagenic activity. This results suggests that a restriction factor other than mA3 may be involved. Studies conducted in 2016 continued to examine hypermutation of the ecotropic MuLV AKV and the involvement of mA3. We have found that AKV harvested from M. dunni cells does not undergo hypermutation on 3T3 cells during an initial infection. However, AKV virions harvested from the initial infection undergo hypermutation upon further infection. This result indicates that AKV virions have acquired a factor from the NIH 3T3 cells that induces G to A hypermutation. Other studies in which AKV infected M. dunni cells were transfected with mA3 or human APOBEC3G (hA3G) indicated that the restriction factors were incorporated into virions. However, hA3G but not mA3 induced G to A hypermutation. These results further suggest that mA3 may not induce hypermutation of AKV in mice.

据估计，人类和小鼠在进化过程中获得了大约4万份逆转录病毒拷贝，其中大约8%的基因组序列起源于逆转录病毒。这些逆转录病毒中的大多数不再是全长，也不编码功能性逆转录病毒。然而，一些内源性逆转录病毒元件在重要的生理作用中发挥作用，如在胚胎发生过程中对宿主基因的转录调节或诱导胎盘-滋养细胞融合。在人类中，HERV-K （HLM-2）内源性逆转录病毒组是最近获得的，并且在人群中具有多态性。这些病毒的表达与许多疾病有关，但尚未确定其致病性。一组小鼠内源性逆转录病毒，称为多嗜性病毒，如HERV-K (HLM-2)，是最近在小鼠中获得的内源性逆转录病毒。它们在小鼠品系中是多态的，并且与许多致病过程有关。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Selective up-regulation of intact, but not defective env RNAs of endogenous modified polytropic retrovirus by the Sgp3 locus of lupus-prone mice.

狼疮易感小鼠的 Sgp3 基因座选择性上调内源性修饰多向逆转录病毒的完整而非缺陷的 env RNA。

DOI：
10.4049/jimmunol.0900263
发表时间：
2009
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Yoshinobu,Kumiko;Baudino,Lucie;Santiago-Raber,Marie-Laure;Morito,Naoki;Dunand-Sauthier,Isabelle;Morley,BernardJ;Evans,LeonardH;Izui,Shozo
通讯作者：
Izui,Shozo

TLR-mediated up-regulation of serum retroviral gp70 is controlled by the Sgp loci of lupus-prone mice.