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Nature Reviews. Microbiology Jan 2022A hallmark of retroviral replication is establishment of the proviral state, wherein a DNA copy of the viral RNA genome is stably incorporated into a host cell... (Review)
Review
A hallmark of retroviral replication is establishment of the proviral state, wherein a DNA copy of the viral RNA genome is stably incorporated into a host cell chromosome. Integrase is the viral enzyme responsible for the catalytic steps involved in this process, and integrase strand transfer inhibitors are widely used to treat people living with HIV. Over the past decade, a series of X-ray crystallography and cryogenic electron microscopy studies have revealed the structural basis of retroviral DNA integration. A variable number of integrase molecules congregate on viral DNA ends to assemble a conserved intasome core machine that facilitates integration. The structures additionally informed on the modes of integrase inhibitor action and the means by which HIV acquires drug resistance. Recent years have witnessed the development of allosteric integrase inhibitors, a highly promising class of small molecules that antagonize viral morphogenesis. In this Review, we explore recent insights into the organization and mechanism of the retroviral integration machinery and highlight open questions as well as new directions in the field.
Topics: Crystallography, X-Ray; DNA, Viral; HIV Integrase; HIV-1; Humans; Integrases; Models, Molecular; Protein Conformation; Retroviridae; Virus Integration
PubMed: 34244677
DOI: 10.1038/s41579-021-00586-9 -
Critical Reviews in Microbiology Nov 2018The human genome contains a large number of retroviral elements acquired over the process of evolution, some of which are specific to primates. However, as many of these... (Review)
Review
The human genome contains a large number of retroviral elements acquired over the process of evolution, some of which are specific to primates. However, as many of these are defective or silenced through epigenetic changes, they were historically considered "junk DNA" and their potential role in human physiology or pathological circumstances have been poorly studied. The most recently acquired, human endogenous retrovirus-K (HERV-K), has multiple copies in the human genome and some of them have complete open reading frames that are transcribed and translated, especially in early embryogenesis. Phylogenetically, HERV-K is considered a supergroup of viruses. One of the subtypes, termed HML-2, seems to be the most active and hence, it is the best studied. Aberrant expression of HML-2 in adult tissues has been associated with certain types of cancer and with neurodegenerative diseases. This review discusses the discovery of these viruses, their classification, structure, regulation and potential for replication, physiological roles, and their involvement in disease pathogenesis. Finally, it presents different therapeutic approaches being considered to target these viruses.
Topics: Animals; Endogenous Retroviruses; Genome, Human; Humans; Retroviridae; Retroviridae Infections; Virus Replication
PubMed: 30318978
DOI: 10.1080/1040841X.2018.1501345 -
Journal of Feline Medicine and Surgery Sep 2020Feline leukaemia virus (FeLV) is a retrovirus of domestic cats worldwide. Cats lacking strong FeLV-specific immunity and undergoing progressive infection commonly... (Review)
Review
PRACTICAL RELEVANCE
Feline leukaemia virus (FeLV) is a retrovirus of domestic cats worldwide. Cats lacking strong FeLV-specific immunity and undergoing progressive infection commonly develop fatal FeLV-associated disease. Many aspects of FeLV infection pathogenesis have been elucidated, some during more recent years using molecular techniques. It is recommended that the FeLV status of every cat is known, since FeLV infection can influence the prognosis and clinical management of every sick cat. Moreover, knowledge of a cat's FeLV status is of epidemiological importance to prevent further spread of the infection.
CLINICAL CHALLENGES
Diagnosing FeLV infection remains challenging due to different outcomes of infection, which can vary over time depending on the balance between the virus and the host's immune system. Furthermore, testing for FeLV infection has become more refined over the years and now includes diagnostic assays for different viral and immunological parameters. Knowledge of FeLV infection pathogenesis, as well as the particulars of FeLV detection methods, is an important prerequisite for correct interpretation of any test results and accurate determination of a cat's FeLV status.
AIMS
The current review presents recent knowledge on FeLV pathogenesis, key features to be determined in FeLV infection, and frequently used FeLV detection methods, and their characteristics and interpretation. An algorithm for the diagnosis of FeLV infection in a single cat, developed by the European Advisory Board on Cat Diseases, is included, and FeLV testing in specific situations is addressed. As well as increasing awareness of this deadly infection in domestic cats, the aim is to contribute diagnostic expertise to allow veterinarians in practice to improve their recognition, and further reduce the prevalence, of FeLV infection.
Topics: Animals; Cat Diseases; Cats; Leukemia Virus, Feline; Retroviridae Infections; Tumor Virus Infections
PubMed: 32845225
DOI: 10.1177/1098612X20941785 -
Annual Review of Immunology Apr 2023Our defenses against infection rely on the ability of the immune system to distinguish invading pathogens from self. This task is exceptionally challenging, if not... (Review)
Review
Our defenses against infection rely on the ability of the immune system to distinguish invading pathogens from self. This task is exceptionally challenging, if not seemingly impossible, in the case of retroviruses that have integrated almost seamlessly into the host. This review examines the limits of innate and adaptive immune responses elicited by endogenous retroviruses and other retroelements, the targets of immune recognition, and the consequences for host health and disease. Contrary to theoretical expectation, endogenous retroelements retain substantial immunogenicity, which manifests most profoundly when their epigenetic repression is compromised, contributing to autoinflammatory and autoimmune disease and age-related inflammation. Nevertheless, recent evidence suggests that regulated immune reactivity to endogenous retroelements is integral to immune system development and function, underpinning cancer immunosurveillance, resistance to infection, and responses to the microbiota. Elucidation of the interaction points with endogenous retroelements will therefore deepen our understanding of immune system function and contribution to disease.
Topics: Humans; Animals; Retroelements; Immunity, Innate; Autoimmune Diseases; Retroviridae
PubMed: 36630597
DOI: 10.1146/annurev-immunol-101721-033341 -
Viruses May 2022This review is an accompaniment to a Special Issue on "Retroviral RNA Processing". It discusses post-transcriptional regulation of retroviruses, ranging from the ancient... (Review)
Review
This review is an accompaniment to a Special Issue on "Retroviral RNA Processing". It discusses post-transcriptional regulation of retroviruses, ranging from the ancient foamy viruses to more modern viruses, such as HIV-1, HTLV-1, Rous sarcoma virus, murine leukemia virus, mouse mammary tumor virus, and Mason-Pfizer monkey virus. This review is not comprehensive. However, it tries to address some of the major questions in the field with examples of how different retroviruses express their genes. It is amazing that a single primary RNA transcript can have so many possible fates: genomic RNA, unspliced mRNA, and up to 50 different alternatively spliced mRNAs. This review will discuss the sorting of RNAs for packaging or translation, RNA nuclear export mechanisms, splicing, translation, RNA modifications, and avoidance of nonsense-mediated RNA decay.
Topics: Active Transport, Cell Nucleus; Animals; Leukemia Virus, Murine; Mice; RNA Processing, Post-Transcriptional; RNA, Messenger; RNA, Viral; Retroviridae
PubMed: 35632854
DOI: 10.3390/v14051113 -
Viruses Jan 2022Stephen Oroszlan received his early education in Hungary, graduating in 1950 from the Technical University in Budapest with a degree in chemical engineering [...].
Stephen Oroszlan received his early education in Hungary, graduating in 1950 from the Technical University in Budapest with a degree in chemical engineering [...].
Topics: History, 20th Century; History, 21st Century; Humans; Male; Retroviridae; Retroviridae Proteins; Viral Protease Inhibitors; Viral Proteases
PubMed: 35215882
DOI: 10.3390/v14020290 -
Bioscience Reports Mar 2022Human T-cell leukemia virus type 1 (HTLV-1) is the only identified oncogenic human retrovirus. HTLV-1 infects approximately 5-10 million people worldwide and is the... (Review)
Review
Human T-cell leukemia virus type 1 (HTLV-1) is the only identified oncogenic human retrovirus. HTLV-1 infects approximately 5-10 million people worldwide and is the infectious cause of adult T-cell leukemia/lymphoma (ATL) and several chronic inflammatory diseases, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), dermatitis, and uveitis. Unlike other oncogenic retroviruses, HTLV-1 does not capture a cellular proto-oncogene or induce proviral insertional mutagenesis. HTLV-1 is a trans-activating retrovirus and encodes accessory proteins that induce cellular transformation over an extended period of time, upwards of several years to decades. Inarguably the most important viral accessory protein involved in transformation is Tax. Tax is a multifunctional protein that regulates several different pathways and cellular processes. This single viral protein is able to modulate viral gene expression, activate NF-κB signaling pathways, deregulate the cell cycle, disrupt apoptosis, and induce genomic instability. The summation of these processes results in cellular transformation and virus-mediated oncogenesis. Interestingly, HTLV-1 also encodes a protein called Hbz from the antisense strand of the proviral genome that counters many Tax functions in the infected cell, such as Tax-mediated viral transcription and NF-κB activation. However, Hbz also promotes cellular proliferation, inhibits apoptosis, and disrupts genomic integrity. In addition to viral proteins, there are other cellular factors such as MEF-2, superoxide-generating NAPDH oxidase 5-α (Nox5α), and PDLIM2 which have been shown to be critical for HTLV-1-mediated T-cell transformation. This review will highlight the important viral and cellular factors involved in HTLV-1 transformation and the available in vitro and in vivo tools used to study this complex process.
Topics: Adult; Basic-Leucine Zipper Transcription Factors; Human T-lymphotropic virus 1; Humans; LIM Domain Proteins; Microfilament Proteins; NF-kappa B; Paraparesis, Tropical Spastic; Retroviridae Proteins; Viral Proteins
PubMed: 35169839
DOI: 10.1042/BSR20211921 -
Current Opinion in Virology Jun 2019During retrovirus maturation, cleavage of the precursor structural Gag polyprotein by the viral protease induces architectural rearrangement of the virus particle from... (Review)
Review
During retrovirus maturation, cleavage of the precursor structural Gag polyprotein by the viral protease induces architectural rearrangement of the virus particle from an immature into a mature, infectious form. The structural rearrangement encapsidates the viral RNA genome in a fullerene capsid, producing a diffusible viral core that can initiate infection upon entry into the cytoplasm of a host cell. Maturation is an important therapeutic window against HIV-1. In this review, we highlight recent breakthroughs in understanding of the structures of retroviral immature and mature capsid lattices that define the boundary conditions of maturation and provide novel insights on capsid transformation. We also discuss emerging insights on encapsidation of the viral genome in the mature capsid, as well as remaining questions for further study.
Topics: Capsid; Capsid Proteins; Genome, Viral; HIV-1; Models, Molecular; Peptide Hydrolases; RNA, Viral; Retroviridae; Virion; Virus Assembly
PubMed: 31185449
DOI: 10.1016/j.coviro.2019.05.004 -
Biochimica Et Biophysica Acta.... Feb 2018Mitochondria play important roles in multiple aspects of viral tumorigenesis. Mitochondrial genomes contribute to the host's genetic background. After viruses enter the... (Review)
Review
Mitochondria play important roles in multiple aspects of viral tumorigenesis. Mitochondrial genomes contribute to the host's genetic background. After viruses enter the cell, they modulate mitochondrial function and thus alter bioenergetics and retrograde signaling pathways. At the same time, mitochondria also regulate and mediate viral oncogenesis. In this context, oncogenesis by oncoviruses like Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human papilloma virus (HPV), Human Immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) will be discussed.
Topics: Animals; Carcinogenesis; Cell Transformation, Neoplastic; Genome, Mitochondrial; HIV; Hepacivirus; Hepatitis B virus; Herpesvirus 4, Human; Humans; Mitochondria; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Papillomaviridae; Retroviridae; Signal Transduction
PubMed: 28962899
DOI: 10.1016/j.bbadis.2017.09.023 -
Viruses Oct 2021Porcine endogenous retroviruses (PERVs) are integrated in the genome of all pigs, and some of them are able to infect human cells. Therefore, PERVs pose a risk for... (Review)
Review
Porcine endogenous retroviruses (PERVs) are integrated in the genome of all pigs, and some of them are able to infect human cells. Therefore, PERVs pose a risk for xenotransplantation, the transplantation of pig cells, tissues, or organ to humans in order to alleviate the shortage of human donor organs. Up to 2021, a huge body of knowledge about PERVs has been accumulated regarding their biology, including replication, recombination, origin, host range, and immunosuppressive properties. Until now, no PERV transmission has been observed in clinical trials transplanting pig islet cells into diabetic humans, in preclinical trials transplanting pig cells and organs into nonhuman primates with remarkable long survival times of the transplant, and in infection experiments with several animal species. Nevertheless, in order to prevent virus transmission to the recipient, numerous strategies have been developed, including selection of PERV-C-free animals, RNA interference, antiviral drugs, vaccination, and genome editing. Furthermore, at present there are no more experimental approaches to evaluate the full risk until we move to the clinic.
Topics: Animals; Endogenous Retroviruses; Gammaretrovirus; Host Specificity; Immunosuppressive Agents; Retroviridae Infections; Swine; Swine Diseases; Transplantation, Heterologous; Zoonoses
PubMed: 34834962
DOI: 10.3390/v13112156