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Viruses Mar 2021I was fortunate to be associated with the lab of Stephen Oroszlan at the US National Cancer Institute from ~1982 until his conversion to Emeritus status in 1995. His lab...
I was fortunate to be associated with the lab of Stephen Oroszlan at the US National Cancer Institute from ~1982 until his conversion to Emeritus status in 1995. His lab made groundbreaking discoveries on retroviral proteins during that time, including many features that could not have been inferred or anticipated from straightforward sequence information. Building on the Oroszlan lab results, my colleagues and I demonstrated that the zinc fingers in nucleocapsid proteins play a crucial role in genomic RNA encapsidation; that the N-terminal myristylation of the Gag proteins of many retroviruses is important for their association with the plasma membrane before particle assembly is completed; and that gammaretroviruses initially synthesize their Env protein as an inactive precursor and then truncate the cytoplasmic tail of the transmembrane protein, activating Env fusogenicity, during virus maturation. We also elucidated several aspects of the mechanism of translational suppression in gene expression in gammaretroviruses; amazingly, this is a fundamentally different mechanism of suppression from that in most other retroviral genera.
Topics: Cell Membrane; History, 21st Century; Retroviridae; Viral Proteins
PubMed: 33809689
DOI: 10.3390/v13030491 -
Nature Reviews. Microbiology Feb 2007All replication-competent retroviruses contain three main reading frames, gag, pol and env, which are used for the synthesis of structural proteins, enzymes and envelope... (Review)
Review
All replication-competent retroviruses contain three main reading frames, gag, pol and env, which are used for the synthesis of structural proteins, enzymes and envelope proteins respectively. Complex retroviruses, such as lentiviruses, also code for regulatory and accessory proteins that have essential roles in viral replication. The concerted expression of these genes ensures the efficient polypeptide production required for the assembly and release of new infectious progeny virions. Retroviral protein synthesis takes place in the cytoplasm and depends exclusively on the translational machinery of the host infected cell. Therefore, not surprisingly, retroviruses have developed RNA structures and strategies to promote robust and efficient expression of viral proteins in a competitive cellular environment.
Topics: Animals; Eukaryotic Cells; Gene Expression Regulation, Viral; Humans; Protein Biosynthesis; RNA, Viral; Retroviridae; Viral Proteins; Virus Replication
PubMed: 17224922
DOI: 10.1038/nrmicro1599 -
Virology May 2015Many important aspects of human retroviral infections cannot be fully evaluated using only in vitro systems or unmodified animal models. An alternative approach involves... (Review)
Review
Many important aspects of human retroviral infections cannot be fully evaluated using only in vitro systems or unmodified animal models. An alternative approach involves the use of humanized mice, which consist of immunodeficient mice that have been transplanted with human cells and/or tissues. Certain humanized mouse models can support robust infection with human retroviruses including different strains of human immunodeficiency virus (HIV) and human T cell leukemia virus (HTLV). These models have provided wide-ranging insights into retroviral biology, including detailed information on primary infection, in vivo replication and pathogenesis, latent/persistent reservoir formation, and novel therapeutic interventions. Here we describe the humanized mouse models that are most commonly utilized to study retroviral infections, and outline some of the important discoveries that these models have produced during several decades of intensive research.
Topics: Animals; Disease Models, Animal; Host-Pathogen Interactions; Humans; Mice, SCID; Retroviridae; Retroviridae Infections; Virus Latency; Virus Replication
PubMed: 25680625
DOI: 10.1016/j.virol.2015.01.017 -
Microbiology Spectrum Oct 2014Retroviruses and LTR retrotransposons are transposable elements that encapsidate the RNAs that are intermediates in the transposition of DNA copies of their genomes... (Review)
Review
Retroviruses and LTR retrotransposons are transposable elements that encapsidate the RNAs that are intermediates in the transposition of DNA copies of their genomes (proviruses), from one cell (or one locus) to another. Mechanistic similarities in DNA transposase enzymes and retroviral/retrotransposon integrases underscore the close evolutionary relationship among these elements. The retroviruses are very ancient infectious agents, presumed to have evolved from Ty3/Gypsy LTR retrotransposons (1), and DNA copies of their sequences can be found embedded in the genomes of most, if not all, members of the tree of life. All retroviruses share a specific gene arrangement and similar replication strategies. However, given their ancestries and occupation of diverse evolutionary niches, it should not be surprising that unique sequences have been acquired in some retroviral genomes and that the details of the mechanism by which their transposition is accomplished can vary. While every step in the retrovirus lifecycle is, in some sense, relevant to transposition, this Chapter focuses mainly on the early phase of retroviral replication, during which viral DNA is synthesized and integrated into its host genome. Some of the initial studies that set the stage for current understanding are highlighted, as well as more recent findings obtained through use of an ever-expanding technological toolbox including genomics, proteomics, and siRNA screening. Persistence in the area of structural biology has provided new insight into conserved mechanisms as well as variations in detail among retroviruses, which can also be instructive.
Topics: DNA Transposable Elements; DNA, Viral; Proviruses; Recombination, Genetic; Retroviridae; Transposases; Virus Integration
PubMed: 26104370
DOI: 10.1128/microbiolspec.MDNA3-0005-2014 -
Poultry Science Aug 1998Three species of avian retrovirus cause disease in poultry: the avian leukosis/sarcoma virus (ALSV), reticuloendotheliosis virus (REV), and lymphoproliferative disease... (Review)
Review
Three species of avian retrovirus cause disease in poultry: the avian leukosis/sarcoma virus (ALSV), reticuloendotheliosis virus (REV), and lymphoproliferative disease virus (LPDV) of turkeys. The ALSV can be classified as slowly transforming viruses, which lack a viral oncogene, and acutely transforming viruses, which possess a viral oncogene. Slowly transforming viruses induce late onset leukoses of the B cell lymphoid, erythroid, and myeloid cell lineages, and other tumors, by viral promoter insertion into the genome of a host cell and activation of a cellular protooncogene. The various acutely transforming leukemia and sarcoma viruses induce leukotic or other tumors rapidly and carry one or anther (sometimes two) viral oncogenes, of which some 15 have been identified. The ALSV fall into six envelope subgroups, A through E, and the recently recognized J subgroup, which induces myeloid leukosis. With the exception of Subgroup E viruses, these viruses spread vertically and horizontally as infectious virions, and are termed exogenous viruses. Subgroup E viruses are usually spread genetically as DNA proviruses (often defective) in host germ cell genome, and are termed endogenous viruses. Several other families of endogenous viruses also exist, one of which, endogenous avian retrovirus (EAV), is related to Subgroup J ALV. Exogenous viruses, and sometimes endogenous viruses, can have detrimental effects on commercially important production traits. Exogenous viruses are currently controlled by virus eradication schemes. Reticuloendotheliosis virus, which lacks a viral oncogene, causes chronic B cell and T-cell lymphomas in chickens, and also chronic lymphomas in turkeys and other species of birds. An acutely transforming variant of REV, Strain T, carries a viral oncogene, and induces reticuloendotheliosis within a few days. In chickens and turkeys, REV spreads vertically and horizontally. No commercial control schemes are operated. In turkeys, LPDV infection has occurred in several countries, where it caused a lymphoproliferative disease of uncertain nature.
Topics: Animals; Cell Differentiation; Chickens; Hematopoietic Stem Cells; Poultry Diseases; Retroviridae; Retroviridae Infections; Turkeys
PubMed: 9706091
DOI: 10.1093/ps/77.8.1204 -
AIDS Reviews 2014Simian immunodeficiency viruses, simian T‑cell lymphotropic viruses, and simian foamy viruses from nonhuman primates have crossed the species barrier to humans at... (Review)
Review
Simian immunodeficiency viruses, simian T‑cell lymphotropic viruses, and simian foamy viruses from nonhuman primates have crossed the species barrier to humans at several time points, leading to the HIV and human T lymphotropic virus epidemic and to sporadic cases of human infections with simian foamy viruses, respectively. Efficient infection and spread in humans differs between simian foamy virus, simian lymphotropic virus, and simian immunodeficiency virus, but seems also to differ among the different viruses from the same simian lineage, as illustrated by the different spread of HIV‑1 M, N O, P or for the different HIV‑2 groups. Among the four HIV‑1 groups, only HIV‑1 group M has spread worldwide, and the actual diversity within HIV‑1 M (subtypes, circulating recombinants) is the result of subsequent evolution and spread in the human population. HIV‑2 only spread to some extent in West Africa, and similarly as for HIV‑1, the nine HIV‑2 groups have also a different epidemic history. Four types of human T lymphotropic virus, type 1 to 4, have been described in humans and for three of them simian counterparts (simian T lymphotropic virus‑1, ‑2, ‑3) have been identified in multiple nonhuman primate species. The majority of human infections are with human T lymphotropic virus‑1, which is present throughout the world as clusters of high endemicity. Humans are susceptible to a wide variety of simian foamy viruses and seem to acquire these viruses more readily than simian immunodeficiency viruses or simian T lymphotropic viruses, but neither signs of disease in humans nor human‑to‑human transmission of simian foamy virus have been documented yet. The current HIV‑1 M epidemic illustrates the impact of a single cross‑species transmission. The recent discovery of HIV‑1 P, HIV‑2 I, new human T lymphotropic virus‑1 and ‑3 variants, as well as simian foamy virus infections in humans in Central Africa, show that our knowledge of genetic diversity and cross‑species transmissions of simian retroviruses is still incomplete.
Topics: Genetic Variation; Humans; Retroviridae; Simian Immunodeficiency Virus
PubMed: 24584106
DOI: No ID Found -
Virology May 2015Proteolytic processing of viral polyproteins is essential for retrovirus infectivity. Retroviral proteases (PR) become activated during or after assembly of the... (Review)
Review
Proteolytic processing of viral polyproteins is essential for retrovirus infectivity. Retroviral proteases (PR) become activated during or after assembly of the immature, non-infectious virion. They cleave viral polyproteins at specific sites, inducing major structural rearrangements termed maturation. Maturation converts retroviral enzymes into their functional form, transforms the immature shell into a metastable state primed for early replication events, and enhances viral entry competence. Not only cleavage at all PR recognition sites, but also an ordered sequence of cleavages is crucial. Proteolysis is tightly regulated, but the triggering mechanisms and kinetics and pathway of morphological transitions remain enigmatic. Here, we outline PR structures and substrate specificities focusing on HIV PR as a therapeutic target. We discuss design and clinical success of HIV PR inhibitors, as well as resistance development towards these drugs. Finally, we summarize data elucidating the role of proteolysis in maturation and highlight unsolved questions regarding retroviral maturation.
Topics: Antiviral Agents; Drug Resistance, Viral; Peptide Hydrolases; Proteolysis; Retroviridae; Substrate Specificity; Viral Proteins; Virion
PubMed: 25816761
DOI: 10.1016/j.virol.2015.03.021 -
Cell Aug 1995
Review
Topics: Amino Acid Sequence; Animals; Genetic Vectors; Humans; Leukemia Virus, Gibbon Ape; Molecular Sequence Data; Receptors, Virus; Retroviridae; Retroviridae Infections
PubMed: 7664331
DOI: 10.1016/0092-8674(95)90024-1 -
Viruses Apr 2023Retroviruses, especially the pathogenic human immunodeficiency virus type 1 (HIV-1), have severely threatened human health for decades. Retroviruses can form stable... (Review)
Review
Retroviruses, especially the pathogenic human immunodeficiency virus type 1 (HIV-1), have severely threatened human health for decades. Retroviruses can form stable latent reservoirs via retroviral DNA integration into the host genome, and then be temporarily transcriptional silencing in infected cells, which makes retroviral infection incurable. Although many cellular restriction factors interfere with various steps of the life cycle of retroviruses and the formation of viral latency, viruses can utilize viral proteins or hijack cellular factors to evade intracellular immunity. Many post-translational modifications play key roles in the cross-talking between the cellular and viral proteins, which has greatly determined the fate of retroviral infection. Here, we reviewed recent advances in the regulation of ubiquitination and SUMOylation in the infection and latency of retroviruses, focusing on both host defense- and virus counterattack-related ubiquitination and SUMOylation system. We also summarized the development of ubiquitination- and SUMOylation-targeted anti-retroviral drugs and discussed their therapeutic potential. Manipulating ubiquitination or SUMOylation pathways by targeted drugs could be a promising strategy to achieve a "sterilizing cure" or "functional cure" of retroviral infection.
Topics: Humans; Sumoylation; Ubiquitination; Retroviridae Infections; Viral Proteins; Retroviridae
PubMed: 37112965
DOI: 10.3390/v15040985 -
Viruses Sep 2019It has now been more than two years since we said our last goodbye to Jan Svoboda (14 [...].
It has now been more than two years since we said our last goodbye to Jan Svoboda (14 [...].
Topics: Humans; Retroviridae; Retroviridae Infections
PubMed: 31491994
DOI: 10.3390/v11090828